Patent Publication Number: US-2017356923-A1

Title: Methods of monitoring adherence to quetiapine therapy

Description:
PRIORITY CLAIM 
     This application is a continuation of U.S. patent application Ser. No. 14/823,734 filed Aug. 11, 2015, which claims priority to U.S. Provisional Patent Application Ser. No. 62/035,687, filed Aug. 11, 2014, the entire contents of which is incorporated herein by reference and relied upon. 
    
    
     TECHNICAL FIELD 
     The present disclosure provides methods for monitoring subject (e.g., patient) adherence to Seroquel® (quetiapine) therapy, for example as a component of treating a subject for a mental health disorder such as schizophrenia, bipolar disorder, and major depressive disorder. 
     BACKGROUND 
     Quetiapine (Seroquel®) is an atypical antipsychotic prescribed for the treatment of acute symptoms of schizophrenia and bipolar disorder. Along with an antidepressant, is is also used to treat major depressive disorder. Nonadherence to antipsychotic medication and substance misuse have recently been reported to be more prevalent among patients with major depressive disorder or bipolar disease than those with schizophrenia. (Millet, et al., American Society of Clinical Pyschopharmacology, poster 58, June 2015). Urine drug testing has been employed by behavioral health clinicians to monitor patient compliance through analysis of drugs and their major metabolites. Typically, adherence to quetiapine therapy is monitored by evaluating levels of quetiapine and one of its plasma metabolites, 7-hydroxy quetiapine (Baselt,  Disposition of Toxic Drugs and Chemicals in Man,  10 th  ed., pp. 1754-1756 (2014)) (see Table 1 for structure). However, these molecules are present in only low levels after dosing, thus false negative monitoring results can be observed. A recent publication demonstrated the number of positives (70.5%) and negatives (29.5%) observed from a population of quetiapine patients prescribed daily dosing of Seroquel® (DeGeorge 2015). Such false negative results can improperly induce a clinician (e.g., a physician or psychiatrist) to alter a compliant subject&#39;s quetiapine therapeutic regimen when no alteration is warranted. Improved methods for assessing and monitoring a subject&#39;s adherence to quetiapine therapy are needed. 
     SUMMARY 
     The present disclosure provides methods for monitoring patient adherence to quetiapine therapy, for example as a component of treating a subject for a mental health disorder such as schizophrenia, bipolar disorder, or major depressive disorder. 
     In certain embodiments, the present disclosure provides a method for monitoring quetiapine therapy in a subject, the method comprising identifying a subject who has been prescribed quetiapine therapy; analyzing a fluid sample of the subject for the presence of a quetiapine metabolite; and identifying the subject as adherent to the prescribed quetiapine therapy if the fluid sample contains the quetiapine metabolite in an amount greater than a threshold level, or as non-adherent if the fluid sample contains no quetiapine metabolite or an amount of the quetiapine metabolite below the threshold level. 
     In some embodiments, the present disclosure provides a method for monitoring quetiapine therapy in a subject, the method comprising identifying a subject who has been prescribed quetiapine therapy; hydrolyzing a fluid sample of the subject; analyzing the hydrolyzed fluid sample for the presence of at least one quetiapine metabolite selected from the group consisting of: quetiapine, quetiapine sulfoxide, 7-hyroxyquetiapine, and quetiapine carboxylic acid; and identifying the subject as adherent to the prescribed quetiapine therapy if the hydrolyzed fluid sample contains the quetiapine metabolite in an amount greater than a threshold level. 
     In one embodiment, the present disclosure provides a method for monitoring quetiapine therapy in a subject comprising of identifying a subject who has been prescribed quetiapine therapy, obtaining a fluid sample from the subject, analyzing the fluid sample for the presence of quetiapine sulfoxide, and identifying the subject as adherent to the prescribed quetiapine therapy if the fluid sample contains quetiapine sulfoxide above a threshold level or non-adherent if the fluid sample contains no quetiapine sulfoxide or an amount of quetiapine sulfoxide below a threshold level. 
     In another embodiment, the present disclosure provides a method for monitoring quetiapine therapy in a subject comprising of identifying a subject who has been prescribed quetiapine therapy, obtaining a fluid sample from the subject, analyzing the fluid sample for the presence of quetiapine carboxylic acid, and identifying the subject as adherent to the prescribed quetiapine therapy if the fluid sample contains quetiapine carboxylic acid above a threshold level but non-adherent if the fluid sample contains no quetiapine carboxylic acid or an amount of quetiapine carboxylic acid below a threshold level. 
     In yet another embodiment, the present disclosure provides a method for monitoring quetiapine therapy in a subject comprising identifying a subject who has been prescribed quetiapine therapy, obtaining a fluid sample from the subject, analyzing the fluid sample for the presence of quetiapine sulfoxide and quetiapine carboxylic acid, and identifying the subject as adherent to the prescribed quetiapine therapy if the fluid sample contains a sum of quetiapine sulfoxide and quetiapine carboxylic acid above a threshold level but non-adherent if the fluid sample contains no quetiapine sulfoxide or quetiapine carboxylic acid or a sum of quetiapine sulfoxide and quetiapine carboxylic acid below a threshold level. 
     In yet another embodiment, the present disclosure provides a method for monitoring quetiapine therapy in a subject comprising of identifying a subject who has been prescribed quetiapine therapy, obtaining a fluid sample from the subject, analyzing the fluid sample for the presence of quetiapine, 7-hydroxy quetiapine, quetiapine sulfoxide, and quetiapine carboxylic acid, and identifying the subject as adherent to the prescribed quetiapine therapy if the fluid sample contains some, if not all, of the metabolites (i.e., parent drug=metabolite number 1) above a threshold level. Or, they can be determined to be adherent if the sum of quetiapine, 7-hydroxy quetiapine, quetiapine sulfoxide, and quetiapine carboxylic acid is above a threshold level but non-adherent if the fluid sample exhibits a sum of quetiapine sulfoxide and quetiapine carboxylic acid below a threshold level. 
     In yet another embodiment, the present disclosure provides a method for monitoring quetiapine therapy in a subject comprising of identifying a subject who has been prescribed quetiapine therapy, obtaining a fluid sample from the subject, analyzing the fluid sample for the presence of quetiapine, 7-hydroxy quetiapine, quetiapine sulfoxide, and quetiapine carboxylic acid, and identifying the subject as adherent to the prescribed quetiapine therapy if the fluid sample contains some, if not all, of the metabolites (i.e., parent drug=metabolite number 1) above a threshold level. As shown below in Table 3, lower doses of quetiapine more readily demonstrate observable levels of quetiapine sulfoxide and quetiapine carboxylic acid. As the dosage increases levels of all metabolites are observed in patient samples, as would be expected. It can also be observed, as shown in Table 21, that upon hydrolysis, even at low doses, the quetiapine and 7-hydroxy quetiapine are more readily observed along with the quetiapine sulfoxide and quetiapine carboxylic acid. However, the quetiapine sulfoxide and quetiapine carboxylic acid appear in greater abundance than the quetiapine and 7-hydroxy quetiapine. Thus, the use of quetiapine sulfoxide and quetiapine carboxylic acid to determine adherence is probably more important at low doses where quetiapine and 7-hydroxy quetiapine are difficult to observe without hydrolysis. 
     In another embodiment, the present disclosure provides a method of evaluating compliance with quetiapine therapy in a subject, the method comprising of obtaining a fluid sample (e.g., urine) from the subject, analyzing the fluid sample for presence or absence of an analyte, and identifying the subject as compliant if the analyte is present in the fluid sample above a threshold level The threshold level can be determined as a function of the analytical method used to assay the analyte or it can be a clinically relevant level below which the data have little clinical meaning. 
     In any of the methods herein, a non-compliant subject can further be counseled as to the importance of compliance and strategies for achieving compliance. 
    
    
     DETAILED DESCRIPTION 
     While the present invention is capable of being embodied in various forms, the description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the invention, and is not intended to limit the invention to the specific embodiments illustrated. Headings are provided for convenience only and are not to be construed to limit the invention in any manner. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. 
     The use of numerical values in the various quantitative values specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word “about.” Also, the disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values recited as well as any ranges that can be formed by such values. Also disclosed herein are any and all ratios (and ranges of any such ratios) that can be formed by dividing a disclosed numeric value into any other disclosed numeric value. Accordingly, the skilled person will appreciate that many such ratios, ranges, and ranges of ratios can be unambiguously derived from the numerical values presented herein and in all instances such ratios, ranges, and ranges of ratios represent various embodiments of the present invention. 
     Quetiapine (Seroquel®) is an atypical antipsychotic prescribed for the treatment of acute symptoms of schizophrenia, bipolar disorder, and major depressive disorder. Quetiapine (2-(2-(4-dibenzo[b,f][1,4]thiazepine-11-yl-1-piperazinyl)ethoxy) ethanol) has a molecular weight of 383.5099 g/mol, and empirical formula of C 21 H 25 N 3 O 2 S, a calculated log P of 1.59 at pH 5.5, a CAS number of 111974-69-7, a mass-to-charge ratio (m/z) of 384.5 when ionized with the addition of a proton (ESI MS), and has a structure shown below: 
     
       
         
         
             
             
         
       
     
     Quetiapine is commercially available as 25 mg, 50 mg, 100 mg, 200 mg, and 400 mg tablets. It is rapidly absorbed after oral administration. Dosing is recommended to be either without food or with a light meal (˜300 calories) as this can increase the bioavailability by ˜20%. The mean elimination half-life is 6 hours. Steady state serum concentrations for quetiapine are typically achieved after 2 days of dosing. 
     Quetiapine is metabolized in the liver primarily by CYP3A4. Metabolism includes oxidative N-dealkylation, hydroxylation of the 7 position on the ring, S-oxidation, and oxidation of the alkyl OH group to the corresponding carboxylic acid. Nearly twenty metabolites of quetiapine have been previously identified including those conjugated to glucuronic acid. Select metabolites of quetiapine are shown in Table 1 below. 
     
       
         
           
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Quetiapine and Select Metabolites Thereof. 
               
               
                   
               
             
            
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Quetiapine 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 7-Hydroxy N-Desalkyl Quetiapine 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Quetiapine Carboxylic Acid 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 7-Hydroxy Quetiapine 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 N-Desalkyl Quetiapine 
               
               
                 (Norquetiapine) 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Quetiapine Sulfoxide 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 O-Desalkyl Quetiapine 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Quetiapine Glucuronide 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 7-Hydroxy Quetiapine Glucuronide 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Quetiapine Sulfoxide Glucuronide 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Quetiapine Carboxylic Acid Glucuronide 
               
               
                   
               
            
           
         
       
     
     Among the various known quetiapine metabolites, the carboxylic acid and the sulfoxide are not biologically active, but have been reported to be “major” metabolites observed in urine (e.g., defined by ≧0% total drug exposure) (Baselt 2014). Metabolites 7-hydroxy quetiapine and N-desalkyl quetiapine are known to be biologically active, but are observable in only small quantities in the urine of in humans. 
     Quetiapine metabolite designated carboxylic acid is the result of oxidation of the terminal alkyl OH group. Together with the sulfoxide, these metabolites have been reported to be primary metabolites in the urine (Baselt 2014). However, earlier work using GC/MS did not use them to monitor quetiapine levels inasmuch as the carboxylic acid has low volatility which is required to maintain the molecule in the gas phase for analysis by GC/MS. The sulfoxide proved to be unstable at temperatures required for GC analysis (Reference?). As such, reference standards for them were not as readily available as for 7-hydroxy quetiapine and N-desalkyl quetiapine. It is noteworthy that quetiapine and the 7-hydroxy, carboxylic acid, and sulfoxide metabolites can also exist as glucuronide conjugates in the urine (see Table 1). 
     Drug adherence has been shown to be particularly low in patients with schizophrenia, bipolar disorder, and major depressive disorder (Millet, et al., American Society of Clinical Pyschopharmacology, Poster 58, June 2015) Urine drug testing has been employed by behavioral health clinicians to monitor patient compliance through analysis of drugs and their major metabolites. 
     In one embodiment, the present disclosure provides a method for monitoring quetiapine therapy in a subject. In some embodiments, the method comprises of identifying a subject who has been prescribed quetiapine therapy, obtaining a fluid sample from the subject, analyzing the fluid sample for the presence of quetiapine carboxylic acid, and identifying the subject as adherent to the prescribed quetiapine therapy if the fluid sample contains quetiapine carboxylic acid and/or any other metabolite or parent drug above a threshold level but non-adherent if the fluid sample contains no quetiapine carboxylic acid or an amount of quetiapine carboxylic acid and/or any other metabolite or parent drug below a threshold level. In some embodiments, the method further comprises counseling the subject on dangers of non-adherence to quetiapine therapy or strategies to achieve compliance if the subject is identified as non-adherent. In some embodiments, the threshold level is a minimum detectable amount of quetiapine carboxylic acid. In some embodiments, the threshold level is about 5 ng/mL to about 500 ng/mL, for example about 5 ng/mL, about 10 ng/mL, about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 125 ng/mL, about 150 ng/mL, about 175 ng/mL, about 200 ng/mL, about 225 ng/mL, about 250 ng/mL, about 275 ng/mL, about 300 ng/mL, about 325 ng/mL, about 350 ng/mL, about 375 ng/mL, about 400 ng/mL, about 425 ng/mL, about 450 ng/mL, about 475 ng/mL, or about 500 ng/mL. In some embodiments, the threshold level is about 5 ng/mL. In some embodiments, the fluid sample is a urine sample. 
     In another embodiment, the present disclosure provides a method for monitoring quetiapine therapy in a subject. In some embodiments, the method comprises of identifying a subject who has been prescribed quetiapine therapy, obtaining a fluid sample from the subject, analyzing the fluid sample for the presence of quetiapine sulfoxide, and identifying the subject as adherent to the prescribed quetiapine therapy if the fluid sample contains quetiapine sulfoxide above a threshold level but non-adherent if the fluid sample contains no quetiapine sulfoxide or an amount of quetiapine sulfoxide below a threshold level. In some embodiments, the method further comprises counseling the subject on dangers of non-adherence to quetiapine therapy if the subject is identified as non-adherent. In some embodiments, the threshold level is a minimum detectable amount of quetiapine sulfoxide. In some embodiments, the threshold level is about 5 ng/mL to about 500 ng/mL, for example about 5 ng/mL, about 10 ng/mL, about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 125 ng/mL, about 150 ng/mL, about 175 ng/mL, about 200 ng/mL, about 225 ng/mL, about 250 ng/mL, about 275 ng/mL, about 300 ng/mL, about 325 ng/mL, about 350 ng/mL, about 375 ng/mL, about 400 ng/mL, about 425 ng/mL, about 450 ng/mL, about 475 ng/mL, or about 500 ng/mL. In some embodiments, the threshold level is about 5 ng/mL. In some embodiments, the fluid sample is a urine sample. 
     In another embodiment, the present disclosure provides a method for monitoring quetiapine therapy in a subject. In some embodiments, the method comprises of identifying a subject who has been prescribed quetiapine therapy, obtaining a fluid sample from the subject, analyzing the fluid sample for the presence of quetiapine sulfoxide and quetiapine carboxylic acid, and identifying the subject as adherent to the prescribed quetiapine therapy if the fluid sample contains a sum of quetiapine sulfoxide and quetiapine carboxylic acid above a threshold level but non-adherent if the fluid sample contains no quetiapine sulfoxide or quetiapine carboxylic acid or a sum of quetiapine sulfoxide and quetiapine carboxylic acid below a threshold level. In some embodiments, the method further comprises counseling the subject on dangers of non-adherence to quetiapine therapy or strategies to achieve compliance if the subject is identified as non-adherent. In some embodiments, the threshold level is a minimum detectable amount of quetiapine sulfoxide or quetiapine carboxylic acid. In some embodiments, the threshold level is about 5 ng/mL to about 500 ng/mL, for example about 5 ng/mL, about 10 ng/mL, about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 125 ng/mL, about 150 ng/mL, about 175 ng/mL, about 200 ng/mL, about 225 ng/mL, about 250 ng/mL, about 275 ng/mL, about 300 ng/mL, about 325 ng/mL, about 350 ng/mL, about 375 ng/mL, about 400 ng/mL, about 425 ng/mL, about 450 ng/mL, about 475 ng/mL, or about 500 ng/mL. In some embodiments, the threshold level is about 10 ng/mL. In some embodiments, the fluid sample is a urine sample. 
     In another embodiment, the present disclosure provides a method for monitoring quetiapine therapy in a subject. In some embodiments, the method comprises of identifying a subject who has been prescribed quetiapine therapy, obtaining a fluid sample from the subject, analyzing the fluid sample for the presence of quetiapine, quetiapine sulfoxide, N-desalkylquetiapine, 7-hyroxyquetiapine, 7-hydroxyquetiapine glucuronide, quetiapine carboxylic acid, quetiapine glucuronide, quetiapine sulfoxide glucuronide, and quetiapine carboxylic acid glucuronide, and identifying the subject as adherent to the prescribed quetiapine therapy if the fluid sample contains a sum of quetiapine, quetiapine sulfoxide, N-desalkylquetiapine, 7-hyroxyquetiapine, 7-hydroxyquetiapine glucuronide, quetiapine carboxylic acid, quetiapine glucuronide, quetiapine sulfoxide glucuronide, and quetiapine carboxylic acid glucuronide above a threshold level but non-adherent if the fluid sample contains a sum of quetiapine sulfoxide and quetiapine carboxylic acid below a threshold level. In some embodiments, the patient can be defined as adherent if any of quetiapine, quetiapine sulfoxide, N-desalkylquetiapine, 7-hyroxyquetiapine, 7-hydroxyquetiapine glucuronide, quetiapine carboxylic acid, quetiapine glucuronide, quetiapine sulfoxide glucuronide, and quetiapine carboxylic acid glucuronide are found in the fluid sample above a threshold. In other embodiments, the patient can be defined as adherent if quetiapine sulfoxide and quetiapine carboxylic acid are found above a threshold at low doses where quetiapine and 7-hydroxy quetiapine are not found. In some embodiments, the method further comprises counseling the subject on dangers of non-adherence to quetiapine therapy or strategies to achieve compliance if the subject is identified as non-adherent. In some embodiments, the threshold level is a minimum detectable amount of quetiapine sulfoxide or quetiapine carboxylic acid. In some embodiments, the threshold level is about 5 ng/mL to about 500 ng/mL, for example about 5 ng/mL, about 10 ng/mL, about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 125 ng/mL, about 150 ng/mL, about 175 ng/mL, about 200 ng/mL, about 225 ng/mL, about 250 ng/mL, about 275 ng/mL, about 300 ng/mL, about 325 ng/mL, about 350 ng/mL, about 375 ng/mL, about 400 ng/mL, about 425 ng/mL, about 450 ng/mL, about 475 ng/mL, or about 500 ng/mL. In some embodiments, the threshold level is about 5 ng/mL. In some embodiments, the fluid sample is a urine sample. 
     In some embodiments, the present disclosure provides a method for monitoring quetiapine therapy in a subject. In some embodiments, the method comprises identifying a subject who has been prescribed quetiapine therapy; analyzing a fluid sample of the subject for the presence of a quetiapine metabolite; and identifying the subject as adherent to the prescribed quetiapine therapy if the fluid sample contains the quetiapine metabolite in an amount greater than a threshold level, or as non-adherent if the fluid sample contains no quetiapine metabolite or an amount of the quetiapine metabolite below the threshold level. In some embodiments, the method further comprising counseling the subject on dangers of non-adherence to quetiapine therapy if the subject is identified as non-adherent. In some embodiments, the threshold level is a minimum detectable amount of the quetiapine metabolite. In some embodiments, the threshold level is about 50 ng/mL, more preferably 20 ng/mL and most preferably 5 ng/mL. In some embodiments, the fluid sample is a urine sample. In some embodiments, the quetiapine metabolite is one or more of: quetiapine, quetiapine sulfoxide, N-desalkylquetiapine, 7-hyroxyquetiapine, 7-hydroxyquetiapine glucuronide, quetiapine carboxylic acid, quetiapine glucuronide, quetiapine sulfoxide glucuronide, and quetiapine carboxylic acid glucuronide. In some embodiments, the quetiapine metabolite is two or more of: quetiapine, quetiapine sulfoxide, N-desalkylquetiapine, 7-hyroxyquetiapine, 7-hydroxyquetiapine glucuronide, quetiapine carboxylic acid, quetiapine glucuronide, quetiapine sulfoxide glucuronide, and quetiapine carboxylic acid glucuronide. In some embodiments, the quetiapine metabolite is three or more of: quetiapine, quetiapine sulfoxide, N-desalkylquetiapine, 7-hyroxyquetiapine, 7-hydroxyquetiapine glucuronide, quetiapine carboxylic acid, quetiapine glucuronide, quetiapine sulfoxide glucuronide, and quetiapine carboxylic acid glucuronide. In some embodiments, the quetiapine metabolite is four or more of: quetiapine, quetiapine sulfoxide, N-desalkylquetiapine, 7-hyroxyquetiapine, 7-hydroxyquetiapine glucuronide, quetiapine carboxylic acid, quetiapine glucuronide, quetiapine sulfoxide glucuronide, and quetiapine carboxylic acid glucuronide. In some embodiments, the quetiapine metabolite is quetiapine, quetiapine sulfoxide, 7-hyroxyquetiapine, and quetiapine carboxylic acid. In some embodiments, the subject is identified as adherent to the prescribed quetiapine therapy if the fluid sample contains quetiapine, quetiapine sulfoxide, 7-hyroxyquetiapine, and quetiapine carboxylic acid in an amount greater than or equal to the threshold value, wherein the threshold value is 5 ng/mL. In some embodiments, the method further comprises contacting the fluid sample with a hydrolyzing enzyme before analyzing the fluid sample for the presence of the quetiapine metabolite. In some embodiments, the hydrolyzing enzyme is a glucuronidase enzyme. In some embodiments, the glucuronidase enzyme is a β-glucuronidase enzyme. In some embodiments, the β-glucuronidase enzyme is a naturally occurring β-glucuronidase enzyme. In other embodiments, the β-glucuronidase enzyme is a recombinant β-glucuronidase enzyme. In some embodiments, the method further comprises generating a report including a statement identifying the subject as adherent or non-adherent. In some embodiments, the report further includes a recommendation to modify the prescribed quetiapine therapy if the subject is identified as non-adherent. In some embodiments, the report includes a recommendation to obtain a genetic test to determine a biological cause for the subject&#39;s non-adherence if the subject is identified as non-adherent. In some embodiments, the recommendation to obtain a genetic test includes a recommendation to obtain a genetic test identifying at least one (e.g., any) genetic variant in the subject&#39;s cytochrome P450 3A4 (CYP3A4) gene resulting in altered drug metabolism. Genetic testing (e.g., genotyping) for metabolic enzymes of the cytochrome P450 family can be used to determine whether a patient has the metabolic capability to handle quetiapine as well as a number of mental health and pain medications. In the exact case of quetiapine, the primary metabolic pathway is through CYP3A4. If the subject is deficient in CYP3A4 capacity, it may be better to prescribe an alternative antipsychotic. If, however, the subject is a normal metabolizer via CYP3A4, he or she may be diverting or misusing their prescription if the determined drug ratio is outside compliance. Rapid metabolizers may also have genetic issues wherein the drug is metabolized so quickly that they might not fit a “normal” standard distribution of drug ratios. Thus, genetic testing can offer rationale for why certain patients appear to be “not adherent” to their prescribed medications. Such a genetic test could therefore reveal a biological cause to quetiapine metabolite ratios that would suggest an otherwise adherent subject is non-adherent. 
     In other embodiments, the present disclosure provides a method for monitoring quetiapine therapy in a subject, the method comprising identifying a subject who has been prescribed quetiapine therapy; hydrolyzing a fluid sample of the subject; analyzing the hydrolyzed fluid sample for the presence of at least one quetiapine metabolite selected from the group consisting of: quetiapine, quetiapine sulfoxide, 7-hyroxyquetiapine, and quetiapine carboxylic acid; and identifying the subject as adherent to the prescribed quetiapine therapy if the hydrolyzed fluid sample contains the quetiapine metabolite in an amount greater than a threshold level. In some embodiments, the step of hydrolyzing the fluid sample comprises contacting the fluid sample with a composition comprising a hydrolyzing enzyme. In some embodiments, the hydrolyzing enzyme is a glucuronidase enzyme. In some embodiments, the glucuronidase enzyme is a β-glucuronidase enzyme. In some embodiments, the β-glucuronidase enzyme is a naturally occurring β-glucuronidase enzyme. In other embodiments, the β-glucuronidase enzyme is a recombinant β-glucuronidase enzyme. In some embodiments, the threshold value is 5 ng/mL. In some embodiments, the method further comprises identifying the subject as non-adherent if the hydrolyzed fluid sample does not contain any one of quetiapine, quetiapine sulfoxide, 7-hyroxyquetiapine, and quetiapine carboxylic acid in an amount above the threshold value. In some embodiments, the method further comprises generating a report including a statement identifying the subject as adherent or non-adherent. In some embodiments, the report further includes a recommendation to modify the prescribed quetiapine therapy if the subject is identified as non-adherent. In some embodiments, the report includes a recommendation to obtain a genetic test to determine a biological cause for the subject&#39;s non-adherence if the subject is identified as non-adherent. In some embodiments, the recommendation to obtain a genetic test includes a recommendation to obtain a genetic test identifying at least one (e.g., any) genetic variant in the subject&#39;s CYP450 enzyme 3A4. 
     In another embodiment, the present disclosure provides a method of evaluating compliance with quetiapine therapy in a subject. In some embodiments, the method comprises of obtaining a fluid sample from the subject, analyzing the fluid sample for presence or absence of an analyte, and identifying the subject as compliant if the analyte is present in the fluid sample. In some embodiments, the analyte comprises quetiapine and/or a quetiapine metabolite or metabolites. In some embodiments, the analyte is selected from the group consisting of quetiapine sulfoxide, quetiapine carboxylic acid, 7-hydroxy quetiapine, N-desalkyl quetiapine, or a combination thereof. In some embodiments, the analyte comprises quetiapine carboxylic acid. In some embodiments, the analyte comprises quetiapine sulfoxide. In some embodiments, the analyte comprises a combination of quetiapine carboxylic acid and quetiapine sulfoxide. In some embodiments, the analyte is considered present in the fluid sample if the analyte is detected above a threshold value. In some embodiments, the threshold value is about 50 ng/mL. In other embodiments, the threshold value is about 25 ng/mL. In still other embodiments, the threshold value is about 5 ng/mL. 
     EXAMPLES 
     Example 1 
     Urine samples of normally metabolizing human subjects who were known to be taking chronic doses of quetiapine were tested for the presence of quetiapine and 7 metabolites. 
     100 μL of each patient specimen was diluted with 450 μL of 250 ng/mL of hydrocodone-D6 (internal standard) in methanol and 350 μL of 0.1% formic acid. Samples were subsequently vortexed and centrifuged prior to the injection of 5 μL of each replicateon the Q-ToF. Each patient sample was analyzed twice to ensure accuracy. 
     In plasma, N-desalkyl quetiapine has been reported to account for 10% of the total radioactivity post oral dosing while quetiapine represents 24% of the total radioactivity, and 7-hydroxy quetiapine represents 11% of the total radioactive dose in the plasma. Excretion studies in humans report that the drug is excreted with 20% in the feces and 73% recovered in the urine. 
     Surprisingly, neither metabolite N-desalkyl quetiapine nor metabolite 7-hydroxy quetiapine was found to be the dominant metabolite excreted through human urine in the majority of samples. Instead, the identity of detectable quetiapine metabolites varies from subject to subject, as shown in Table 2 below: 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Quetiapine Metabolite Distribution in Human Urine 
               
            
           
           
               
               
            
               
                   
                 Analyte 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 7-Hydroxy 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 Desalkyl 
                 7-Hydroxy 
                 Carboxy 
                 N-Desalkyl 
                 O-Desalkyl 
                   
                 Quetiapine 
                 Quetiapine 
               
               
                 Patient 
                 Quetiapine 
                 Quetiapine 
                 Quetiapine 
                 Quetiapine 
                 Quetiapine 
                 Quetiapine 
                 Glucuronide 
                 Sulfoxide 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 1 
                 7.27 
                 0.65 
                 6.71 
                 8.48 
                 0.00 
                 0.19 
                 0.40 
                 1.81 
               
               
                 2 
                 23.21 
                 7.76 
                 43.61 
                 16.66 
                 0.73 
                 2.08 
                 6.23 
                 10.81 
               
               
                 3 
                 5.22 
                 0.00 
                 27.86 
                 11.15 
                 1.08 
                 8.21 
                 0.02 
                 2.02 
               
               
                 4 
                 10.36 
                 6.86 
                 26.14 
                 4.18 
                 0.23 
                 1.87 
                 5.23 
                 12.90 
               
               
                 5 
                 0.39 
                 0.08 
                 5.36 
                 0.80 
                 0.00 
                 0.08 
                 0.52 
                 0.23 
               
               
                 6 
                 5.16 
                 1.23 
                 34.19 
                 2.94 
                 0.00 
                 0.58 
                 3.16 
                 4.10 
               
               
                 7 
                 2.25 
                 0.86 
                 10.95 
                 4.09 
                 0.04 
                 0.85 
                 1.06 
                 2.22 
               
               
                 8 
                 7.24 
                 0.54 
                 51.31 
                 13.44 
                 0.00 
                 0.31 
                 4.74 
                 1.79 
               
               
                 9 
                 7.95 
                 3.73 
                 13.07 
                 8.81 
                 0.30 
                 0.98 
                 1.86 
                 6.54 
               
               
                 10 
                 5.22 
                 0.35 
                 3.60 
                 5.20 
                 0.00 
                 0.12 
                 0.29 
                 1.09 
               
               
                 11 
                 3.21 
                 0.15 
                 8.23 
                 2.09 
                 0.00 
                 0.01 
                 1.18 
                 0.58 
               
               
                 12 
                 0.04 
                 0.04 
                 0.75 
                 0.08 
                 0.00 
                 0.06 
                 0.09 
                 0.12 
               
               
                   
               
               
                 *Values are analyte responses relative to an internal standard that was present in every sample. This is meant to relate relative abundance only and not meant for quantitation. 
               
            
           
         
       
     
     As shown above, several metabolites were present in all 12 of these random patient positive samples. This includes quetiapine, 7-hydroxyquetiapine, 7-hydroxy desalkyl quetiapine, N-desalkyl quetiapine, quetiapine sulfoxide, and carboxy quetiapine (quetiapine carboxylic acid). Quetiapine carboxylic acid and quetiapine sulfoxide were present in significant amounts in every sample. 
     These data demonstrate that regardless of prescribed dose, quetiapine metabolite quetiapine carboxylic acid (carboxy quetiapine) provides a greater level of sensitivity and consistency among subjects on quetiapine therapy, and therefore provides a superior urine analyte for evaluation of a subject&#39;s compliance with a quetiapine therapeutic regimen. 
     These data demonstrate that quetiapine metabolite quetiapine sulfoxide provides a greater level of sensitivity and consistency among subjects on quetiapine therapy, and therefore provides a superior urine analyte for evaluation of a subject&#39;s compliance with a quetiapine therapeutic regimen. 
     These data demonstrate that quetiapine metabolites quetiapine carboxylic acid (carboxy quetiapine) and quetiapine sulfoxide together provide a greater level of sensitivity and consistency among subjects on quetiapine therapy, and therefore provides superior urine analytes for evaluation of a subject&#39;s compliance with a quetiapine therapeutic regimen. 
     Example 2 
     The urine of 16 patients who were prescribed 25 mg of Seroquel® (quetiapine) was tested for compliance (Table 3). 100 μL of each patient specimen was diluted with 50 μL of 1.6 μg/mL of quetiapine-D8 (internal standard) in methanol and 350 μL of 0.1% formic acid. Samples were subsequently vortexed and centrifuged prior to the injection of 5 μL on the QQQ. Each patient sample was analyzed twice to ensure accuracy. 
     The preponderance of quetiapine carboxylic acid and quetiapine sulfoxide in the urine as the major metabolic urine compounds is shown in Table 3. Assuming 16 opportunities to determine the patient to be either positive or negative for Seroquel® dosing, the use of quetiapine carboxylic acid and quetiapine sulfoxide resulted in 100% correct identification of those taking the prescribed medicine. The data in Table 4 demonstrate the “normal” nature of the sample validity criteria (i.e., pH, specific gravity, and creatinine). Without the quetiapine carboxylic acid and quetiapine sulfoxide metabolites, only ˜63% were determined to be positive solely by the parent compound quetiapine and ˜69% were determined to be positive when using the parent compound quetiapine in conjunction with 7-hydroxy quetiapine. Clearly, the use of all 4 analytes results in 100% correct identification of those prescribed this dose. Thus, use of quetiapine carboxylic acid and quetiapine sulfoxide as a urine biomarker at this low dose adds value to compliance monitoring for Seroquel®. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Test Results from Patients Prescribed 25 mg/day Seroquel ® (all parent and 
               
               
                 metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
                 All 4 
               
               
                 Subject 
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
                 mets 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 A 
                 1.007 
                 7.9 
                 45.4 
                 ND 
                 ND 
                 94 
                 22 
                 + 
               
               
                 B 
                 1.022 
                 5.5 
                 273.7 
                 ND 
                 ND 
                 9 
                 ND 
                 + 
               
               
                 C 
                 1.010 
                 7.2 
                 80.2 
                 5 
                 ND 
                 493 
                 202 
                 + 
               
               
                 D 
                 1.009 
                 8.0 
                 53.8 
                 40 
                 18 
                 492 
                 343 
                 + 
               
               
                 E 
                 1.012 
                 6.3 
                 106.9 
                 ND 
                 ND 
                 17 
                 8 
                 + 
               
               
                 F 
                 1.016 
                 5.8 
                 242.5 
                 125 
                 61 
                 1844 
                 3738 
                 + 
               
               
                 G 
                 1.009 
                 7.7 
                 66.5 
                 ND 
                 ND 
                 138 
                 34 
                 + 
               
               
                 H 
                 1.003 
                 7.0 
                 34.4 
                 ND 
                 6 
                 82 
                 59 
                 + 
               
               
                 I 
                 1.012 
                 6.8 
                 141.9 
                 19 
                 5 
                 1998 
                 300 
                 + 
               
               
                 J 
                 1.013 
                 5.2 
                 152.0 
                 33 
                 59 
                 4470 
                 1411 
                 + 
               
               
                 K 
                 1.004 
                 7.1 
                 43.4 
                 19 
                 7 
                 2977 
                 3050 
                 + 
               
               
                 L 
                 1.008 
                 6.4 
                 59.0 
                 22 
                 18 
                 2877 
                 2679 
                 + 
               
               
                 M 
                 1.013 
                 7.1 
                 193.9 
                 196 
                 38 
                 5681 
                 517 
                 + 
               
               
                 N 
                 1.005 
                 6.2 
                 43.6 
                 ND 
                 ND 
                 60 
                 11 
                 + 
               
               
                 O 
                 1.006 
                 6.6 
                 25.9 
                 14 
                 17 
                 570 
                 101 
                 + 
               
               
                 P 
                 1.016 
                 6.8 
                 193.5 
                 23 
                 29 
                 1308 
                 1017 
                 + 
               
               
                   
               
               
                 ND: Indicates that the listed parent or metabolite compound was either not detected or detected below the established cut-off of 5 ng/mL indicating a negative result for that particular subject. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Sample Validity and Urine Results Summary at 25 mg/day (all parent and 
               
               
                 metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
               
               
                   
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Average 
                 1.010 
                 6.7 
                 109.8 
                 49.8 
                 25.5 
                 1444.3 
                 899.4 
               
               
                 Standard 
                 0.005 
                 0.8 
                 77.3 
                 58.4 
                 19.8 
                 1695.1 
                 1207.6 
               
               
                 Deviation 
               
               
                 Maximum 
                 1.022 
                 8.0 
                 273.7 
                 196.4 
                 61.2 
                 5681.4 
                 3738.2 
               
               
                 Value 
               
               
                 Median 
                 1.010 
                 6.8 
                 73.4 
                 22.8 
                 17.5 
                 531.7 
                 299.5 
               
               
                 Value 
               
               
                 Minimum 
                 1.003 
                 5.2 
                 25.9 
                 5.3 
                 5.0 
                 8.7 
                 8.4 
               
               
                 Value 
               
               
                   
               
            
           
         
       
     
     Example 3 
     The urine of 45 patients who were prescribed 50 mg of Seroquel® (quetiapine) was tested for compliance (Table 5). 100 μL of each patient specimen was diluted with 50 μL of 1.6 μg/mL of quetiapine-D8 (internal standard) in methanol and 350 μL of 0.1% formic acid. Samples were subsequently vortexed and centrifuged prior to the injection of 5 μL on the QQQ. 
     The preponderance of quetiapine carboxylic acid and quetiapine sulfoxide in the urine as the major metabolic urine compounds is shown in Table 5. Assuming 45 opportunities to determine the patient to be either positive or negative for Seroquel® dosing, the use of quetiapine carboxylic acid and quetiapine sulfoxide resulted in ˜96% correct identification of those taking the prescribed medicine. The data in Table 6 demonstrate the “normal” nature of the sample validity criteria (i.e., pH, specific gravity, and creatinine). Without the quetiapine carboxylic acid and quetiapine sulfoxide metabolites, only ˜58% were determined to be positive solely by the parent compound quetiapine and ˜67% were determined to be positive when using the parent compound quetiapine in conjunction with 7-hydroxy quetiapine. However, the use of all 4 analytes results in 100% correctly determined to be positive. Thus, use of quetiapine carboxylic acid and quetiapine sulfoxide as a urine biomarker at this low dose adds value to compliance monitoring for Seroquel®. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Test Results from Patients Prescribed 50 mg/day Seroquel ® (all parent and 
               
               
                 metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
                 All 4 
               
               
                 Subject 
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
                 mets 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Q 
                 1.014 
                 6.4 
                 43.0 
                 1271 
                 1188 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 S 
                 1.012 
                 5.1 
                 107.0 
                 ND 
                 ND 
                 19 
                 ND 
                 + 
               
               
                 T 
                 1.013 
                 6.9 
                 162.9 
                 ND 
                 ND 
                 6 
                 ND 
                 + 
               
               
                 U 
                 1.004 
                 5.4 
                 30.6 
                 153 
                 145 
                 &gt;5000 
                 1929 
                 + 
               
               
                 V 
                 1.006 
                 5.7 
                 55.3 
                 26 
                 28 
                 334 
                 1551 
                 + 
               
               
                 W 
                 1.003 
                 7.1 
                 31.6 
                 ND 
                 ND 
                 5 
                 ND 
                 + 
               
               
                 X 
                 1.003 
                 6.7 
                 38.1 
                 ND 
                 ND 
                 70 
                 35 
                 + 
               
               
                 Y 
                 1.011 
                 8.2 
                 81.6 
                 ND 
                 5 
                 3272 
                 153 
                 + 
               
               
                 Z 
                 1.010 
                 7.5 
                 64.9 
                 22 
                 68 
                 &gt;5000 
                 398 
                 + 
               
               
                 AA 
                 1.003 
                 6.6 
                 24.5 
                 ND 
                 ND 
                 195 
                 27 
                 + 
               
               
                 AB 
                 1.021 
                 5.0 
                 230.7 
                 268 
                 49 
                 &gt;5000 
                 3410 
                 + 
               
               
                 AC 
                 1.006 
                 5.2 
                 37.7 
                 14 
                 6 
                 1570 
                 244 
                 + 
               
               
                 AD 
                 1.018 
                 6.7 
                 250.2 
                 7 
                 ND 
                 443 
                 269 
                 + 
               
               
                 AF 
                 1.010 
                 5.6 
                 72.1 
                 ND 
                 9 
                 ND 
                 ND 
                 + 
               
               
                 AG 
                 1.009 
                 8.4 
                 94.4 
                 ND 
                 ND 
                 7 
                 ND 
                 + 
               
               
                 AH 
                 1.004 
                 7.1 
                 41.9 
                 8 
                 18 
                 &gt;5000 
                 156 
                 + 
               
               
                 AI 
                 1.013 
                 5.6 
                 69.1 
                 19 
                 27 
                 2892 
                 879 
                 + 
               
               
                 AJ 
                 1.014 
                 5.8 
                 114.4 
                 ND 
                 ND 
                 5 
                 ND 
                 + 
               
               
                 AK 
                 1.022 
                 6.3 
                 188.1 
                 62 
                 75 
                 4845 
                 2693 
                 + 
               
               
                 AL 
                 1.014 
                 4.9 
                 186.1 
                 ND 
                 ND 
                 12 
                 ND 
                 + 
               
               
                 AM 
                 1.015 
                 5.7 
                 110.7 
                 11 
                 15 
                 691 
                 471 
                 + 
               
               
                 AN 
                 1.006 
                 7.4 
                 146.6 
                 35 
                 108 
                 &gt;5000 
                 1437 
                 + 
               
               
                 AO 
                 1.006 
                 6.0 
                 50.9 
                 32 
                 ND 
                 419 
                 230 
                 + 
               
               
                 AP 
                 1.006 
                 8.1 
                 53.4 
                 ND 
                 ND 
                 10 
                 ND 
                 + 
               
               
                 AQ 
                 1.019 
                 5.8 
                 253.6 
                 1118 
                 694 
                 &gt;5000 
                 740 
                 + 
               
               
                 AR 
                 1.015 
                 6.5 
                 100.6 
                 ND 
                 ND 
                 26 
                 ND 
                 + 
               
               
                 AS 
                 1.007 
                 6.9 
                 23.0 
                 6 
                 5 
                 97 
                 1061 
                 + 
               
               
                 AT 
                 1.010 
                 7.9 
                 148.1 
                 44 
                 25 
                 549 
                 1313 
                 + 
               
               
                 AU 
                 1.018 
                 5.2 
                 133.5 
                 243 
                 33 
                 ND 
                 ND 
                 + 
               
               
                 AV 
                 1.013 
                 6.7 
                 110.1 
                 86 
                 8 
                 1591 
                 3226 
                 + 
               
               
                 AX 
                 1.006 
                 6.7 
                 48.1 
                 ND 
                 ND 
                 129 
                 65 
                 + 
               
               
                 AY 
                 1.016 
                 6.3 
                 217.6 
                 169 
                 58 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 AZ 
                 1.016 
                 5.5 
                 92.3 
                 361 
                 298 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 BA 
                 1.017 
                 5.2 
                 159.2 
                 79 
                 39 
                 1328 
                 &gt;5000 
                 + 
               
               
                 BB 
                 1.006 
                 7.7 
                 49.6 
                 38 
                 24 
                 2114 
                 1521 
                 + 
               
               
                 BC 
                 1.015 
                 6.7 
                 160.0 
                 21 
                 24 
                 &gt;5000 
                 306 
                 + 
               
               
                 BD 
                 1.003 
                 6.7 
                 18.7 
                 ND 
                 ND 
                 147 
                 37 
                 + 
               
               
                 BE 
                 1.006 
                 6.4 
                 83.7 
                 221 
                 75 
                 &gt;5000 
                 2675 
                 + 
               
               
                 BF 
                 1.013 
                 6.1 
                 54.2 
                 ND 
                 ND 
                 67 
                 15 
                 + 
               
               
                 BG 
                 1.008 
                 7.8 
                 40.8 
                 ND 
                 6 
                 132 
                 26 
                 + 
               
               
                 BH 
                 1.015 
                 5.4 
                 108.8 
                 23 
                 10 
                 415 
                 129 
                 + 
               
               
                 BI 
                 1.009 
                 8.2 
                 91.1 
                 ND 
                 ND 
                 81 
                 29 
                 + 
               
               
                 BJ 
                 1.009 
                 6.6 
                 78.2 
                 ND 
                 ND 
                 70 
                 ND 
                 + 
               
               
                 BL 
                 1.005 
                 7.3 
                 54.0 
                 ND 
                 12 
                 637 
                 113 
                 + 
               
               
                 BM 
                 1.007 
                 7.3 
                 128.2 
                 9 
                 77 
                 1136 
                 709 
                 + 
               
               
                   
               
               
                 ND: Indicates that the listed parent or metabolite compound was either not detected or detected below the established cut-off of 5 ng/mL indicating a negative result for that particular subject. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Sample Validity and Urine Results Summary at 50 mg/day (all parent and 
               
               
                 metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
               
               
                   
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Average 
                 1.011 
                 6.5 
                 98.6 
                 167 
                 112 
                 729 
                 862 
               
               
                 Standard 
                 0.005 
                 1.0 
                 62.5 
                 312 
                 246 
                 1119 
                 1002 
               
               
                 Deviation 
               
               
                 Maximum 
                 1.022 
                 8.4 
                 253.6 
                 1271 
                 1188 
                 &gt;5000 
                 &gt;5000 
               
               
                 Value 
               
               
                 Median 
                 1.010 
                 6.6 
                 83.7 
                 36 
                 28 
                 171 
                 352 
               
               
                 Value 
               
               
                 Minimum 
                 1.003 
                 4.9 
                 18.7 
                 6 
                 5 
                 5 
                 15 
               
               
                 Value 
               
               
                   
               
            
           
         
       
     
     Example 4 
     The urine of 75 patients who were prescribed 100 mg of Seroquel® (quetiapine) was tested for compliance (Table 7). 100 μL of each patient specimen was diluted with 50 μL of 1.6 μg/mL of quetiapine-D8 (internal standard) in methanol and 350 μL of 0.1% formic acid. Samples were subsequently vortexed and centrifuged prior to the injection of 5 μL on the QQQ. 
     The preponderance of quetiapine carboxylic acid and quetiapine sulfoxide in the urine as the major metabolic urine compounds is shown in Table 7. Assuming 75 opportunities to determine the patient to be either positive or negative for Seroquel® dosing, the use of quetiapine carboxylic acid and quetiapine sulfoxide resulted in ˜99% correct identification of those taking the prescribed medicine. The data in Table 8 demonstrate the “normal” nature of the sample validity criteria (i.e., pH, specific gravity, and creatinine). Without the quetiapine carboxylic acid and quetiapine sulfoxide metabolites, only ˜76% were determined to be positive solely by the parent compound quetiapine and ˜81% were determined to be positive when using the parent compound quetiapine in conjunction with 7-hydroxy quetiapine. However, again, the use of all 4 analytes correctly determines 100% of prescribed patients at this does. Thus, use of quetiapine carboxylic acid and quetiapine sulfoxide as a urine biomarker at this dose does add value to compliance monitoring for Seroquel®. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Test Results from Patients Prescribed 100 mg/day Seroquel ® (all parent and 
               
               
                 metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
                 All 4 
               
               
                 Subject 
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
                 mets 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 BN 
                 1.016 
                 4.6 
                 245.5 
                 &gt;5000 
                 1286 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 BO 
                 1.011 
                 6.4 
                 120.3 
                 ND 
                 ND 
                 98 
                 11 
                 + 
               
               
                 BP 
                 1.020 
                 5.0 
                 227.0 
                 191 
                 70 
                 &gt;5000 
                 2611 
                 + 
               
               
                 BQ 
                 1.005 
                 5.4 
                 52.7 
                 331 
                 40 
                 &gt;5000 
                 843 
                 + 
               
               
                 BR 
                 1.006 
                 5.6 
                 62.0 
                 267 
                 125 
                 &gt;5000 
                 2305 
                 + 
               
               
                 BS 
                 1.015 
                 5.9 
                 209.2 
                 428 
                 420 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 BT 
                 1.012 
                 6.2 
                 82.7 
                 14 
                 7 
                 2321 
                 442 
                 + 
               
               
                 BU 
                 1.018 
                 5.9 
                 233.4 
                 ND 
                 ND 
                 26 
                 17 
                 + 
               
               
                 BV 
                 1.012 
                 5.6 
                 103.3 
                 ND 
                 ND 
                 22 
                 7 
                 + 
               
               
                 BW 
                 1.011 
                 6.9 
                 172.2 
                 17 
                 11 
                 &gt;5000 
                 765 
                 + 
               
               
                 BX 
                 1.014 
                 5.9 
                 187.3 
                 15 
                 18 
                 1554 
                 659 
                 + 
               
               
                 BY 
                 1.005 
                 8.0 
                 107.5 
                 17 
                 51 
                 &gt;5000 
                 2143 
                 + 
               
               
                 BZ 
                 1.014 
                 6.2 
                 185.7 
                 199 
                 183 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 CA 
                 1.009 
                 5.7 
                 58.0 
                 ND 
                 ND 
                 47 
                 8 
                 + 
               
               
                 CB 
                 1.003 
                 7.9 
                 30.4 
                 ND 
                 6 
                 ND 
                 ND 
                 + 
               
               
                 CC 
                 1.011 
                 6.7 
                 69.0 
                 59 
                 171 
                 &gt;5000 
                 1918 
                 + 
               
               
                 CD 
                 1.018 
                 5.5 
                 221.9 
                 138 
                 89 
                 &gt;5000 
                 4782 
                 + 
               
               
                 CE 
                 1.009 
                 7.7 
                 133.8 
                 ND 
                 8 
                 1689 
                 207 
                 + 
               
               
                 CF 
                 1.014 
                 6.0 
                 126.4 
                 233 
                 1996 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 CG 
                 1.013 
                 5.8 
                 90.6 
                 ND 
                 357 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 CH 
                 1.018 
                 6.1 
                 203.1 
                 ND 
                 258 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 CI 
                 1.008 
                 7.1 
                 50.3 
                 ND 
                 ND 
                 &gt;5000 
                 130 
                 + 
               
               
                 CJ 
                 1.005 
                 7.0 
                 74.5 
                 26 
                 10 
                 &gt;5000 
                 265 
                 + 
               
               
                 CK 
                 1.012 
                 5.9 
                 138.1 
                 39 
                 ND 
                 1123 
                 1100 
                 + 
               
               
                 CL 
                 1.009 
                 4.9 
                 105.1 
                 77 
                 71 
                 2816 
                 2998 
                 + 
               
               
                 CM 
                 1.012 
                 6.3 
                 128.5 
                 ND 
                 ND 
                 73 
                 7 
                 + 
               
               
                 CN 
                 1.004 
                 7.0 
                 27.8 
                 29 
                 12 
                 3065 
                 420 
                 + 
               
               
                 CO 
                 1.009 
                 5.2 
                 75.4 
                 7 
                 5 
                 834 
                 185 
                 + 
               
               
                 CP 
                 1.005 
                 6.3 
                 59.4 
                 13 
                 24 
                 515 
                 349 
                 + 
               
               
                 CQ 
                 1.018 
                 5.6 
                 193.4 
                 194 
                 230 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 CR 
                 1.008 
                 7.0 
                 97.1 
                 26 
                 34 
                 &gt;5000 
                 506 
                 + 
               
               
                 CS 
                 1.009 
                 7.3 
                 127.4 
                 135 
                 31 
                 &gt;5000 
                 1722 
                 + 
               
               
                 CT 
                 1.013 
                 6.8 
                 161.5 
                 ND 
                 ND 
                 9 
                 ND 
                 + 
               
               
                 CU 
                 1.014 
                 5.4 
                 126.3 
                 412 
                 106 
                 3639 
                 &gt;5000 
                 + 
               
               
                 CV 
                 1.019 
                 5.9 
                 377.5 
                 438 
                 188 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 CW 
                 1.013 
                 5.2 
                 193.5 
                 ND 
                 ND 
                 8 
                 ND 
                 + 
               
               
                 CX 
                 1.011 
                 7.0 
                 153.5 
                 43 
                 94 
                 2444 
                 &gt;5000 
                 + 
               
               
                 CY 
                 1.009 
                 7.9 
                 146.9 
                 69 
                 27 
                 4405 
                 ND 
                 + 
               
               
                 CZ 
                 1.011 
                 7.6 
                 101.6 
                 9 
                 21 
                 4491 
                 1152 
                 + 
               
               
                 DA 
                 1.010 
                 7.2 
                 86.6 
                 ND 
                 ND 
                 16 
                 176 
                 + 
               
               
                 DB 
                 1.015 
                 5.3 
                 172.0 
                 169 
                 53 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 DC 
                 1.011 
                 6.9 
                 66.0 
                 268 
                 95 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 DD 
                 1.014 
                 7.5 
                 121.9 
                 305 
                 85 
                 &gt;5000 
                 3044 
                 + 
               
               
                 DE 
                 1.009 
                 6.2 
                 108.7 
                 265 
                 150 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 DF 
                 1.009 
                 4.6 
                 151.6 
                 803 
                 159 
                 2927 
                 &gt;5000 
                 + 
               
               
                 DG 
                 1.009 
                 5.2 
                 87.9 
                 19 
                 20 
                 971 
                 1621 
                 + 
               
               
                 DH 
                 1.016 
                 5.1 
                 192.3 
                 314 
                 265 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 DI 
                 1.016 
                 6.2 
                 150.2 
                 136 
                 65 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 DJ 
                 1.016 
                 5.6 
                 238.1 
                 234 
                 77 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 DK 
                 1.010 
                 7.1 
                 91.9 
                 6 
                 5 
                 1416 
                 1862 
                 + 
               
               
                 DL 
                 1.013 
                 7.3 
                 122.3 
                 8 
                 ND 
                 102 
                 124 
                 + 
               
               
                 DM 
                 1.012 
                 7.6 
                 107.1 
                 6 
                 ND 
                 &gt;5000 
                 901 
                 + 
               
               
                 DN 
                 1.006 
                 6.5 
                 39.7 
                 43 
                 24 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 DO 
                 1.019 
                 4.8 
                 193.7 
                 28 
                 50 
                 284 
                 &gt;5000 
                 + 
               
               
                 DP 
                 1.013 
                 5.4 
                 175.4 
                 22 
                 53 
                 336 
                 &gt;5000 
                 + 
               
               
                 DQ 
                 1.010 
                 5.7 
                 86.7 
                 49 
                 100 
                 2802 
                 &gt;5000 
                 + 
               
               
                 DR 
                 1.008 
                 5.6 
                 42.6 
                 ND 
                 ND 
                 119 
                 192 
                 + 
               
               
                 DS 
                 1.019 
                 5.4 
                 172.2 
                 9 
                 49 
                 1321 
                 1131 
                 + 
               
               
                 DT 
                 1.011 
                 6.4 
                 130.5 
                 76 
                 482 
                 &gt;5000 
                 ND 
                 + 
               
               
                 DU 
                 1.012 
                 6.0 
                 230.3 
                 328 
                 183 
                 ND 
                 &gt;5000 
                 + 
               
               
                 DV 
                 1.006 
                 7.3 
                 64.2 
                 131 
                 338 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 DW 
                 1.010 
                 5.8 
                 127.8 
                 328 
                 145 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 DX 
                 1.018 
                 5.7 
                 257.1 
                 ND 
                 ND 
                 15 
                 ND 
                 + 
               
               
                 DY 
                 1.008 
                 5.3 
                 86.8 
                 91 
                 14 
                 866 
                 528 
                 + 
               
               
                 DZ 
                 1.009 
                 5.4 
                 86.4 
                 52 
                 24 
                 407 
                 738 
                 + 
               
               
                 EA 
                 1.004 
                 5.8 
                 25.3 
                 ND 
                 ND 
                 28 
                 13 
                 + 
               
               
                 EB 
                 1.017 
                 6.5 
                 180.9 
                 10 
                 7 
                 1612 
                 220 
                 + 
               
               
                 EC 
                 1.019 
                 5.9 
                 149.1 
                 230 
                 27 
                 &gt;5000 
                 1256 
                 + 
               
               
                 ED 
                 1.013 
                 6.1 
                 113.8 
                 ND 
                 ND 
                 10 
                 ND 
                 + 
               
               
                 EE 
                 1.011 
                 6.6 
                 133.9 
                 312 
                 301 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 EF 
                 1.021 
                 5.3 
                 169.8 
                 ND 
                 ND 
                 46 
                 9 
                 + 
               
               
                 EG 
                 1.005 
                 7.5 
                 52.0 
                 22 
                 54 
                 666 
                 980 
                 + 
               
               
                 EH 
                 1.005 
                 7.0 
                 23.4 
                 26 
                 37 
                 1525 
                 780 
                 + 
               
               
                 EI 
                 1.027 
                 5.8 
                 372.6 
                 49 
                 39 
                 2168 
                 326 
                 + 
               
               
                 EJ 
                 1.017 
                 5.8 
                 188.5 
                 53 
                 28 
                 2602 
                 742 
                 + 
               
               
                   
               
               
                 ND: Indicates that the listed parent or metabolite compound was either not detected or detected below the established cut-off of 5 ng/mL indicating a negative result for that particular subject. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Sample Validity and Urine Results Summary at 100 mg/day (all parent and 
               
               
                 metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
               
               
                   
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Average 
                 1.012 
                 6.2 
                 134.1 
                 140 
                 153 
                 1235 
                 935 
               
               
                 Standard 
                 0.005 
                 0.9 
                 71.2 
                 155 
                 309 
                 1295 
                 1023 
               
               
                 Deviation 
               
               
                 Maximum 
                 1.027 
                 8.0 
                 377.5 
                 &gt;5000 
                 1996 
                 &gt;5000 
                 &gt;5000 
               
               
                 Value 
               
               
                 Median 
                 1.011 
                 6.0 
                 126.4 
                 64 
                 54 
                 850 
                 659 
               
               
                 Value 
               
               
                 Minimum 
                 1.003 
                 4.6 
                 23.4 
                 6 
                 5 
                 8 
                 7 
               
               
                 Value 
               
               
                   
               
            
           
         
       
     
     Example 5 
     The urine of 11 patients who were prescribed 150 mg of Seroquel® (quetiapine) was tested for compliance (Table 9). 100 μL of each patient specimen was diluted with 50 μL of 1.6 μg/mL of quetiapine-D8 (internal standard) in methanol and 350 μL of 0.1% formic acid. Samples were subsequently vortexed and centrifuged prior to the injection of 5 μL on the QQQ. Each patient sample was analyzed twice to ensure accuracy. 
     The preponderance of quetiapine carboxylic acid and quetiapine sulfoxide in the urine as the major metabolic urine compounds is shown in Table 9. Assuming 12 opportunities to determine the patient to be either positive or negative for Seroquel® dosing, the use of quetiapine carboxylic acid and quetiapine sulfoxide resulted in ˜100% correct identification of those taking the prescribed medicine. The data in Table 10 demonstrate the “normal” nature of the sample validity criteria (i.e., pH, specific gravity, and creatinine). Without the quetiapine carboxylic acid and quetiapine sulfoxide metabolites, only ˜82% were determined to be positive solely by the parent compound quetiapine and ˜82% were determined to be positive when using the parent compound quetiapine in conjunction with 7-hydroxy quetiapine. However, again, the use of all 4 analytes correctly determines 100% of prescribed patients at this does. Thus, use of quetiapine carboxylic acid and quetiapine sulfoxide as a urine biomarker at this dose does add value to compliance monitoring for Seroquel®. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Test Results from Patients Prescribed 150 mg/day Seroquel ® (all parent and 
               
               
                 metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
                 All 4 
               
               
                 Subject 
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
                 mets 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 EK 
                 1.011 
                 6.9 
                 165.9 
                 36 
                 86 
                 &gt;5000 
                 813 
                 + 
               
               
                 EL 
                 1.016 
                 6.5 
                 151.2 
                 20 
                 150 
                 4611 
                 834 
                 + 
               
               
                 EM 
                 1.004 
                 7.7 
                 25.4 
                 12 
                 6 
                 2296 
                 356 
                 + 
               
               
                 EN 
                 1.009 
                 7.5 
                 85.7 
                 79 
                 48 
                 &gt;5000 
                 4511 
                 + 
               
               
                 EO 
                 1.020 
                 5.7 
                 170.9 
                 666 
                 152 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 EP 
                 1.005 
                 4.9 
                 43.9 
                 12 
                 37 
                 511 
                 480 
                 + 
               
               
                 EQ 
                 1.005 
                 7.3 
                 104.4 
                 120 
                 121 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 ER 
                 1.002 
                 6.9 
                 17.3 
                 ND 
                 ND 
                 80 
                 30 
                 + 
               
               
                 ES 
                 1.013 
                 7.2 
                 150.6 
                 48 
                 ND 
                 4136 
                 610 
                 + 
               
               
                 EV 
                 1.009 
                 5.8 
                 78.3 
                 ND 
                 ND 
                 23 
                 28 
                 + 
               
               
                 EW 
                 1.006 
                 7.9 
                 64.8 
                 8 
                 16 
                 4653 
                 451 
                 + 
               
               
                   
               
               
                 ND: Indicates that the listed parent or metabolite compound was either not detected or detected below the established cut-off of 5 ng/mL indicating a negative result for that particular subject. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Sample Validity and Urine Results Summary at 150 mg/day (all parent and 
               
               
                 metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
               
               
                   
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Average 
                 1.009 
                 6.8 
                 96.2 
                 111 
                 77 
                 2330 
                 901 
               
               
                 Standard 
                 0.005 
                 0.9 
                 53.8 
                 199 
                 55 
                 1984 
                 1305 
               
               
                 Deviation 
               
               
                 Maximum 
                 1.020 
                 7.9 
                 170.9 
                 666 
                 152 
                 &gt;5000 
                 &gt;5000 
               
               
                 Value 
               
               
                 Median 
                 1.009 
                 6.9 
                 85.7 
                 36 
                 67 
                 2296 
                 480 
               
               
                 Value 
               
               
                 Minimum 
                 1.002 
                 4.9 
                 17.3 
                 8 
                 6 
                 23 
                 28 
               
               
                 Value 
               
               
                   
               
            
           
         
       
     
     Example 6 
     The urine of 59 patients who were prescribed 200 mg of Seroquel® (quetiapine) was tested for compliance (Table 11). 100 μL of each patient specimen was diluted with 50 μL of 1.6 μg/mL of quetiapine-D8 (internal standard) in methanol and 350 μL of 0.1% formic acid. Samples were subsequently vortexed and centrifuged prior to the injection of 5 μL on the QQQ. 
     The preponderance of quetiapine carboxylic acid and quetiapine sulfoxide in the urine as the major metabolic urine compounds is shown in Table 11. Assuming 59 opportunities to determine the patient to be either positive or negative for Seroquel® dosing, the use of quetiapine carboxylic acid and quetiapine sulfoxide resulted in ˜100% correct identification of those taking the prescribed medicine. The data in Table 11 demonstrate the “normal” nature of the sample validity criteria (i.e., pH, specific gravity, and creatinine). Without the quetiapine carboxylic acid and quetiapine sulfoxide metabolites, only ˜75% were determined to be positive solely by the parent compound quetiapine and ˜83% were determined to be positive when using the parent compound quetiapine in conjunction with 7-hydroxy quetiapine. However, when all 4 analytes are used to assess adherence, the result is 100% as per prescription. Thus, use of quetiapine carboxylic acid and quetiapine sulfoxide as a urine biomarker at this dose does add value to compliance monitoring for Seroquel®. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Test Results from Patients Prescribed 200 mg/day Seroquel ® (all parent 
               
               
                 and metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
                 All 4 
               
               
                 Subject 
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
                 mets 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 EX 
                 1.003 
                 5.1 
                 42.7 
                 6 
                 ND 
                 76 
                 74 
                 + 
               
               
                 EY 
                 1.005 
                 6.4 
                 74.0 
                 17 
                 243 
                 &gt;5000 
                 696 
                 + 
               
               
                 FA 
                 1.012 
                 5.2 
                 143.3 
                 182 
                 34 
                 1179 
                 &gt;5000 
                 + 
               
               
                 FB 
                 1.010 
                 7.8 
                 219.4 
                 100 
                 178 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 FC 
                 1.007 
                 7.7 
                 91.6 
                 368 
                 236 
                 &gt;5000 
                 3376 
                 + 
               
               
                 FE 
                 1.009 
                 6.9 
                 164.9 
                 67 
                 335 
                 &gt;5000 
                 4792 
                 + 
               
               
                 FF 
                 1.010 
                 5.7 
                 150.5 
                 ND 
                 ND 
                 22 
                 ND 
                 + 
               
               
                 FG 
                 1.007 
                 6.3 
                 134.7 
                 74 
                 336 
                 &gt;5000 
                 4490 
                 + 
               
               
                 FH 
                 1.017 
                 5.5 
                 275.9 
                 20 
                 21 
                 1305 
                 797 
                 + 
               
               
                 FI 
                 1.011 
                 6.1 
                 144.7 
                 538 
                 430 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 FJ 
                 1.011 
                 6.4 
                 115.2 
                 143 
                 2066 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 FK 
                 1.015 
                 6.7 
                 98.9 
                 ND 
                 37 
                 11 
                 ND 
                 + 
               
               
                 FL 
                 1.013 
                 6.3 
                 175.9 
                 2322 
                 3844 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 FM 
                 1.007 
                 7.5 
                 121.0 
                 ND 
                 46 
                 3224 
                 95 
                 + 
               
               
                 FN 
                 1.005 
                 7.6 
                 126.1 
                 411 
                 293 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 FO 
                 1.010 
                 5.8 
                 65.6 
                 9 
                 81 
                 947 
                 730 
                 + 
               
               
                 FP 
                 1.013 
                 6.2 
                 116.2 
                 19 
                 102 
                 &gt;5000 
                 1058 
                 + 
               
               
                 FQ 
                 1.005 
                 7.4 
                 60.2 
                 5 
                 39 
                 1781 
                 543 
                 + 
               
               
                 FR 
                 1.019 
                 5.6 
                 177.5 
                 ND 
                 20 
                 383 
                 368 
                 + 
               
               
                 FS 
                 1.002 
                 6.7 
                 29.6 
                 ND 
                 ND 
                 25 
                 ND 
                 + 
               
               
                 FT 
                 1.006 
                 5.4 
                 27.9 
                 73 
                 10 
                 1355 
                 414 
                 + 
               
               
                 FU 
                 1.012 
                 6.9 
                 318.9 
                 ND 
                 18 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 FV 
                 1.012 
                 6.5 
                 192.1 
                 208 
                 262 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 FW 
                 1.017 
                 4.9 
                 326.9 
                 315 
                 29 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 FX 
                 1.006 
                 6.8 
                 66.8 
                 97 
                 5 
                 &gt;5000 
                 2971 
                 + 
               
               
                 GA 
                 1.013 
                 6.1 
                 123.8 
                 22 
                 13 
                 1378 
                 361 
                 + 
               
               
                 GB 
                 1.009 
                 7.0 
                 110.1 
                 ND 
                 ND 
                 179 
                 ND 
                 + 
               
               
                 GC 
                 1.005 
                 5.1 
                 56.7 
                 9 
                 9 
                 1302 
                 143 
                 + 
               
               
                 GD 
                 1.006 
                 5.9 
                 37.4 
                 261 
                 178 
                 4523 
                 &gt;5000 
                 + 
               
               
                 GE 
                 1.004 
                 8.6 
                 38.2 
                 64 
                 51 
                 2163 
                 2289 
                 + 
               
               
                 GF 
                 1.016 
                 6.2 
                 128.8 
                 187 
                 262 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 GG 
                 1.015 
                 5.7 
                 185.5 
                 222 
                 116 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 GH 
                 1.009 
                 6.6 
                 150.6 
                 44 
                 86 
                 &gt;5000 
                 1209 
                 + 
               
               
                 GI 
                 1.018 
                 7.0 
                 204.9 
                 62 
                 168 
                 &gt;5000 
                 2195 
                 + 
               
               
                 GJ 
                 1.018 
                 5.8 
                 229.0 
                 159 
                 9 
                 ND 
                 &gt;5000 
                 + 
               
               
                 GK 
                 1.012 
                 6.2 
                 173.0 
                 ND 
                 ND 
                 5 
                 ND 
                 + 
               
               
                 GM 
                 1.017 
                 5.8 
                 110.0 
                 198 
                 151 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 GN 
                 1.005 
                 6.2 
                 77.1 
                 33 
                 44 
                 3801 
                 &gt;5000 
                 + 
               
               
                 GO 
                 1.016 
                 5.6 
                 160.2 
                 286 
                 88 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 GQ 
                 1.014 
                 6.5 
                 156.8 
                 14 
                 19 
                 &gt;5000 
                 946 
                 + 
               
               
                 GR 
                 1.009 
                 5.2 
                 141.0 
                 277 
                 100 
                 504 
                 3488 
                 + 
               
               
                 GS 
                 1.015 
                 5.5 
                 95.9 
                 26 
                 ND 
                 461 
                 1280 
                 + 
               
               
                 GT 
                 1.018 
                 5.2 
                 143.2 
                 229 
                 69 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 GU 
                 1.005 
                 7.1 
                 50.6 
                 ND 
                 16 
                 3620 
                 27 
                 + 
               
               
                 GV 
                 1.021 
                 5.2 
                 221.7 
                 ND 
                 ND 
                 5 
                 15 
                 + 
               
               
                 GW 
                 1.006 
                 7.8 
                 73.4 
                 65 
                 34 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 GX 
                 1.014 
                 6.3 
                 201.9 
                 24 
                 163 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 GY 
                 1.020 
                 6.0 
                 208.0 
                 69 
                 252 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 GZ 
                 1.014 
                 5.6 
                 129.4 
                 55 
                 138 
                 1197 
                 &gt;5000 
                 + 
               
               
                 HA 
                 1.017 
                 6.2 
                 314.6 
                 ND 
                 ND 
                 5 
                 ND 
                 + 
               
               
                 HB 
                 1.010 
                 7.4 
                 127.0 
                 13 
                 34 
                 3265 
                 343 
                 + 
               
               
                 HC 
                 1.006 
                 7.3 
                 56.1 
                 ND 
                 ND 
                 12 
                 ND 
                 + 
               
               
                 HD 
                 1.007 
                 8.1 
                 105.2 
                 19 
                 25 
                 4501 
                 321 
                 + 
               
               
                 HE 
                 1.019 
                 5.5 
                 275.3 
                 ND 
                 ND 
                 9 
                 ND 
                 + 
               
               
                 HF 
                 1.006 
                 6.0 
                 29.0 
                 139 
                 110 
                 &gt;5000 
                 2954 
                 + 
               
               
                 HG 
                 1.009 
                 5.6 
                 83.5 
                 ND 
                 ND 
                 86 
                 11 
                 + 
               
               
                 HH 
                 1.018 
                 5.2 
                 235.3 
                 ND 
                 ND 
                 23 
                 ND 
                 + 
               
               
                 HI 
                 1.012 
                 5.4 
                 89.7 
                 387 
                 153 
                 &gt;5000 
                 4234 
                 + 
               
               
                 HJ 
                 1.003 
                 6.8 
                 21.9 
                 196 
                 37 
                 &gt;5000 
                 1261 
                 + 
               
               
                   
               
               
                 ND: Indicates that the listed parent or metabolite compound was either not detected or detected below the established cut-off of 5 ng/mL indicating a negative result for that particular subject. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Sample Validity and Urine Results Summary at 200 mg/day (all parent and 
               
               
                 metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
               
               
                   
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Average 
                 1.011 
                 6.3 
                 135.7 
                 183 
                 234 
                 1245 
                 1430 
               
               
                 Standard 
                 0.005 
                 0.9 
                 75.5 
                 351 
                 611 
                 1440 
                 1465 
               
               
                 Deviation 
               
               
                 Maximum 
                 1.021 
                 8.6 
                 326.9 
                 2322 
                 3844 
                 &gt;5000 
                 &gt;5000 
               
               
                 Value 
               
               
                 Median 
                 1.011 
                 6.2 
                 127.0 
                 73 
                 86 
                 726 
                 797 
               
               
                 Value 
               
               
                 Minimum 
                 1.002 
                 4.9 
                 21.9 
                 5 
                 5 
                 5 
                 11 
               
               
                 Value 
               
               
                   
               
            
           
         
       
     
     Example 7 
     The urine of 59 patients who were prescribed 300 mg of Seroquel® (quetiapine) was tested for compliance (Table 13). 100 μL of each patient specimen was diluted with 50 μL of 1.6 μg/mL of quetiapine-D8 (internal standard) in methanol and 350 μL of 0.1% formic acid. Samples were subsequently vortexed and centrifuged prior to the injection of 5 μL on the QQQ. 
     The preponderance of quetiapine carboxylic acid and quetiapine sulfoxide in the urine as the major metabolic urine compounds is shown in Table 13. Assuming 58 opportunities to determine the patient to be either positive or negative for Seroquel® dosing, the use of quetiapine carboxylic acid and quetiapine sulfoxide resulted in ˜100% correct identification of those taking the prescribed medicine. The data in Table 14 demonstrate the “normal” nature of the sample validity criteria (i.e., pH, specific gravity, and creatinine). Without the quetiapine carboxylic acid and quetiapine sulfoxide metabolites, ˜86% were determined to be positive solely by the parent compound quetiapine and ˜92% were determined to be positive when using the parent compound quetiapine in conjunction with 7-hydroxy quetiapine. Use of all 4 analytes results in 100% identification of those taking the prescribed medicine. Thus, use of quetiapine carboxylic acid and quetiapine sulfoxide as a urine biomarker at this dose does add value to compliance monitoring for Seroquel®. 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Test Results from Patients Prescribed 300 mg/day Seroquel ® (all parent 
               
               
                 and metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
                 All 4 
               
               
                 Subject 
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
                 mets 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 HI 
                 1.019 
                 5.4 
                 266.9 
                 978 
                 809 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 HJ 
                 1.007 
                 5.9 
                 103.0 
                 42 
                 200 
                 &gt;5000 
                 2356 
                 + 
               
               
                 HK 
                 1.012 
                 5.7 
                 110.8 
                 ND 
                 ND 
                 63 
                 ND 
                 + 
               
               
                 HL 
                 1.014 
                 7.5 
                 129.7 
                 ND 
                 ND 
                 122 
                 35 
                 + 
               
               
                 HM 
                 1.017 
                 5.7 
                 109.3 
                 19 
                 21 
                 1048 
                 489 
                 + 
               
               
                 HN 
                 1.006 
                 7.0 
                 45.5 
                 39 
                 795 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 HO 
                 1.009 
                 6.2 
                 97.6 
                 223 
                 273 
                 &gt;5000 
                 4046 
                 + 
               
               
                 HP 
                 1.008 
                 6.9 
                 56.4 
                 8 
                 ND 
                 808 
                 181 
                 + 
               
               
                 HQ 
                 1.010 
                 6.3 
                 118.8 
                 269 
                 133 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 HR 
                 1.013 
                 5.4 
                 99.7 
                 4574 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 HS 
                 1.018 
                 5.8 
                 176.7 
                 755 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 HT 
                 1.003 
                 6.6 
                 36.9 
                 44 
                 113 
                 &gt;5000 
                 1612 
                 + 
               
               
                 HU 
                 1.007 
                 6.2 
                 44.8 
                 42 
                 73 
                 &gt;5000 
                 1330 
                 + 
               
               
                 HV 
                 1.012 
                 5.8 
                 95.7 
                 200 
                 149 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 HW 
                 1.010 
                 5.4 
                 126.2 
                 462 
                 504 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 HX 
                 1.024 
                 8.9 
                 46.3 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 HY 
                 1.018 
                 6.0 
                 139.4 
                 917 
                 1961 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 HZ 
                 1.019 
                 5.7 
                 112.9 
                 196 
                 370 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 IA 
                 1.006 
                 5.2 
                 70.9 
                 80 
                 100 
                 &gt;5000 
                 1909 
                 + 
               
               
                 IB 
                 1.004 
                 7.3 
                 51.2 
                 121 
                 170 
                 &gt;5000 
                 4538 
                 + 
               
               
                 IC 
                 1.004 
                 8.1 
                 84.1 
                 18 
                 69 
                 &gt;5000 
                 1414 
                 + 
               
               
                 ID 
                 1.007 
                 6.1 
                 68.2 
                 394 
                 686 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 IE 
                 1.009 
                 6.4 
                 93.1 
                 ND 
                 52 
                 636 
                 367 
                 + 
               
               
                 IF 
                 1.011 
                 6.2 
                 110.3 
                 ND 
                 200 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 IG 
                 1.014 
                 5.5 
                 128.3 
                 ND 
                 ND 
                 3610 
                 858 
                 + 
               
               
                 IH 
                 1.014 
                 6.0 
                 255.1 
                 361 
                 63 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 II 
                 1.007 
                 7.7 
                 84.2 
                 1237 
                 84 
                 &gt;5000 
                 2043 
                 + 
               
               
                 IJ 
                 1.012 
                 7.0 
                 161.0 
                 569 
                 211 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 IK 
                 1.008 
                 7.7 
                 93.0 
                 873 
                 2034 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 IL 
                 1.004 
                 8.1 
                 35.9 
                 29 
                 40 
                 &gt;5000 
                 339 
                 + 
               
               
                 IM 
                 1.011 
                 6.6 
                 109.4 
                 347 
                 379 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 IN 
                 1.006 
                 5.7 
                 26.5 
                 177 
                 90 
                 &gt;5000 
                 1390 
                 + 
               
               
                 IP 
                 1.010 
                 7.6 
                 121.4 
                 ND 
                 9 
                 994 
                 95 
                 + 
               
               
                 IQ 
                 1.006 
                 7.3 
                 56.1 
                 55 
                 313 
                 &gt;5000 
                 4135 
                 + 
               
               
                 IS 
                 1.010 
                 6.5 
                 136.4 
                 38 
                 10 
                 &gt;5000 
                 1662 
                 + 
               
               
                 IT 
                 1.003 
                 7.0 
                 20.7 
                 9 
                 8 
                 3008 
                 3343 
                 + 
               
               
                 IU 
                 1.022 
                 5.3 
                 288.4 
                 486 
                 280 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 IV 
                 1.005 
                 7.8 
                 25.0 
                 26 
                 67 
                 4772 
                 &gt;5000 
                 + 
               
               
                 IW 
                 1.019 
                 6.2 
                 311.4 
                 740 
                 418 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 IX 
                 1.012 
                 5.6 
                 120.2 
                 205 
                 46 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 IY 
                 1.022 
                 5.6 
                 178.0 
                 852 
                 191 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 IZ 
                 1.009 
                 6.3 
                 180.3 
                 ND 
                 ND 
                 114 
                 56 
                 + 
               
               
                 JA 
                 1.011 
                 6.8 
                 109.5 
                 7 
                 50 
                 1517 
                 520 
                 + 
               
               
                 JB 
                 1.017 
                 6.9 
                 183.7 
                 &gt;5000 
                 1326 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 JC 
                 1.011 
                 7.2 
                 104.7 
                 31 
                 9 
                 3973 
                 2387 
                 + 
               
               
                 JD 
                 1.004 
                 7.9 
                 83.3 
                 10 
                 18 
                 &gt;5000 
                 2610 
                 + 
               
               
                 JE 
                 1.018 
                 5.7 
                 186.7 
                 2138 
                 1006 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 JF 
                 1.006 
                 5.7 
                 90.1 
                 243 
                 287 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 JG 
                 1.021 
                 5.8 
                 373.0 
                 127 
                 73 
                 3152 
                 3093 
                 + 
               
               
                 JI 
                 1.016 
                 7.1 
                 83.6 
                 16 
                 24 
                 1648 
                 376 
                 + 
               
               
                 JJ 
                 1.004 
                 5.3 
                 34.3 
                 530 
                 169 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 JK 
                 1.007 
                 7.3 
                 73.2 
                 17 
                 28 
                 &gt;5000 
                 447 
                 + 
               
               
                 JL 
                 1.011 
                 5.5 
                 114.4 
                 442 
                 101 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 JM 
                 1.008 
                 6.4 
                 82.0 
                 109 
                 100 
                 &gt;5000 
                 3087 
                 + 
               
               
                 JN 
                 1.016 
                 5.3 
                 111.8 
                 ND 
                 ND 
                 126 
                 17 
                 + 
               
               
                 JO 
                 1.011 
                 5.8 
                 150.8 
                 695 
                 410 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 JP 
                 1.006 
                 8.4 
                 109.9 
                 52 
                 225 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 JQ 
                 1.014 
                 6.3 
                 166.0 
                 67 
                 29 
                 &gt;5000 
                 947 
                 + 
               
               
                 JR 
                 1.010 
                 6.2 
                 84.3 
                 56 
                 25 
                 935 
                 686 
                 + 
               
               
                   
               
               
                 ND: Indicates that the listed parent or metabolite compound was either not detected or detected below the established cut-off of 5 ng/mL indicating a negative result for that particular subject. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 Sample Validity and Urine Results Summary at 300 mg/day (all parent and 
               
               
                 metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
               
               
                   
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Average 
                 1.011 
                 6.5 
                 116.4 
                 407 
                 296 
                 1658 
                 1546 
               
               
                 Standard 
                 0.005 
                 0.9 
                 70.3 
                 727 
                 441 
                 1493 
                 1327 
               
               
                 Deviation 
               
               
                 Maximum 
                 1.024 
                 8.9 
                 373.0 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
               
               
                 Value 
               
               
                 Median 
                 1.010 
                 6.2 
                 109.3 
                 177 
                 123 
                 1021 
                 1360 
               
               
                 Value 
               
               
                 Minimum 
                 1.003 
                 5.2 
                 20.7 
                 7 
                 8 
                 63 
                 17 
               
               
                 Value 
               
               
                   
               
            
           
         
       
     
     Example 8 
     The urine of 41 patients who were prescribed 400 mg of Seroquel® (quetiapine) was tested for compliance (Table 15). 100 μL of each patient specimen was diluted with 50 μL of 1.6 μg/mL of quetiapine-D8 (internal standard) in methanol and 350 μL of 0.1% formic acid. Samples were subsequently vortexed and centrifuged prior to the injection of 5 μL on the QQQ. 
     The preponderance of quetiapine carboxylic acid and quetiapine sulfoxide in the urine as the major metabolic urine compounds is shown in Table 15. Assuming 41 opportunities to determine the patient to be either positive or negative for Seroquel® dosing, the use of quetiapine carboxylic acid and quetiapine sulfoxide resulted in ˜100% correct identification of those taking the prescribed medicine. The data in Table 16 demonstrate the “normal” nature of the sample validity criteria (i.e., pH, specific gravity, and creatinine). Without the quetiapine carboxylic acid and quetiapine sulfoxide metabolites, ˜73% were determined to be positive solely by the parent compound quetiapine and ˜80% were determined to be positive when using the parent compound quetiapine in conjunction with 7-hydroxy quetiapine. Using all 4 analytes resulted in 100% correct identification of those taking the prescribed medicine. Thus, use of quetiapine carboxylic acid and quetiapine sulfoxide as a urine biomarker at this dose does add value to compliance monitoring for Seroquel®. 
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 Test Results from Patients Prescribed 400 mg/day Seroquel ® (all parent 
               
               
                 and metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
                 All 4 
               
               
                 Subject 
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
                 mets 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 JS 
                 1.008 
                 5.7 
                 78.0 
                 128 
                 394 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 JT 
                 1.007 
                 7.7 
                 148.9 
                 29 
                 376 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 JU 
                 1.009 
                 5.6 
                 87.1 
                 ND 
                 ND 
                 9 
                 ND 
                 + 
               
               
                 JW 
                 1.010 
                 5.8 
                 92.8 
                 ND 
                 ND 
                 496 
                 47 
                 + 
               
               
                 JX 
                 1.011 
                 5.8 
                 144.7 
                 560 
                 876 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 JY 
                 1.008 
                 7.6 
                 98.8 
                 77 
                 324 
                 &gt;5000 
                 4484 
                 + 
               
               
                 JZ 
                 1.011 
                 5.7 
                 59.8 
                 73 
                 58 
                 &gt;5000 
                 3198 
                 + 
               
               
                 KA 
                 1.008 
                 7.5 
                 60.3 
                 ND 
                 29 
                 935 
                 46 
                 + 
               
               
                 KB 
                 1.006 
                 7.7 
                 113.8 
                 45 
                 235 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 KC 
                 1.011 
                 6.7 
                 166.7 
                 ND 
                 ND 
                 13 
                 ND 
                 + 
               
               
                 KD 
                 1.007 
                 7.3 
                 26.3 
                 42 
                 86 
                 &gt;5000 
                 2943 
                 + 
               
               
                 KE 
                 1.014 
                 5.6 
                 168.1 
                 ND 
                 ND 
                 328 
                 5 
                 + 
               
               
                 KG 
                 1.003 
                 7.3 
                 48.7 
                 304 
                 580 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 KH 
                 1.015 
                 6.3 
                 249.2 
                 1137 
                 958 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 KI 
                 1.015 
                 5.5 
                 206.3 
                 104 
                 133 
                 &gt;5000 
                 4464 
                 + 
               
               
                 KJ 
                 1.017 
                 5.8 
                 95.9 
                 ND 
                 ND 
                 28 
                 12 
                 + 
               
               
                 KK 
                 1.013 
                 6.4 
                 86.3 
                 11 
                 8 
                 519 
                 874 
                 + 
               
               
                 KL 
                 1.011 
                 6.6 
                 96.7 
                 ND 
                 ND 
                 24 
                 ND 
                 + 
               
               
                 KM 
                 1.008 
                 7.8 
                 48.9 
                 ND 
                 ND 
                 10 
                 6 
                 + 
               
               
                 KN 
                 1.017 
                 6.0 
                 285.5 
                 ND 
                 217 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 KQ 
                 1.005 
                 6.9 
                 44.1 
                 101 
                 64 
                 &gt;5000 
                 2027 
                 + 
               
               
                 KR 
                 1.002 
                 6.5 
                 23.8 
                 ND 
                 10 
                 1179 
                 10 
                 + 
               
               
                 KS 
                 1.015 
                 6.0 
                 205.8 
                 138 
                 159 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 KT 
                 1.012 
                 6.0 
                 153.3 
                 1616 
                 311 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 KU 
                 1.008 
                 5.9 
                 50.8 
                 763 
                 234 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 KV 
                 1.018 
                 5.7 
                 288.7 
                 120 
                 39 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 KW 
                 1.004 
                 7.6 
                 82.3 
                 7 
                 32 
                 523 
                 &gt;5000 
                 + 
               
               
                 KX 
                 1.014 
                 7.1 
                 119.6 
                 ND 
                 ND 
                 70 
                 136 
                 + 
               
               
                 KZ 
                 1.012 
                 5.7 
                 213.3 
                 112 
                 148 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 LA 
                 1.006 
                 5.7 
                 45.4 
                 159 
                 341 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 LB 
                 1.010 
                 8.2 
                 67.0 
                 141 
                 63 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 LC 
                 1.004 
                 7.2 
                 43.6 
                 19 
                 86 
                 3850 
                 &gt;5000 
                 + 
               
               
                 LD 
                 1.003 
                 6.5 
                 24.7 
                 37 
                 27 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 LF 
                 1.003 
                 5.7 
                 25.3 
                 819 
                 157 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 LG 
                 1.024 
                 5.4 
                 351.8 
                 601 
                 1097 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 LH 
                 1.014 
                 5.5 
                 147.7 
                 49 
                 13 
                 4563 
                 955 
                 + 
               
               
                 LI 
                 1.010 
                 6.6 
                 148.3 
                 159 
                 150 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 LJ 
                 1.008 
                 7.9 
                 96.4 
                 27 
                 31 
                 &gt;5000 
                 848 
                 + 
               
               
                 LK 
                 1.004 
                 7.2 
                 22.7 
                 234 
                 32 
                 &gt;5000 
                 1839 
                 + 
               
               
                 LM 
                 1.015 
                 6.1 
                 134.7 
                 784 
                 208 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 LN 
                 1.015 
                 6.5 
                 212.7 
                 233 
                 89 
                 &gt;5000 
                 2618 
                 + 
               
               
                   
               
               
                 ND: Indicates that the listed parent or metabolite compound was either not detected or detected below the established cut-off of 5 ng/mL indicating a negative result for that particular subject. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 Sample Validity and Urine Results Summary at 400 mg/day (all parent and 
               
               
                 metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
               
               
                   
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Average 
                 1.010 
                 6.5 
                 118.7 
                 288 
                 229 
                 896 
                 1442 
               
               
                 Standard 
                 0.005 
                 0.8 
                 80.1 
                 380 
                 273 
                 1403 
                 1540 
               
               
                 Deviation 
               
               
                 Maximum 
                 1.024 
                 8.2 
                 351.8 
                 1616 
                 1097 
                 &gt;5000 
                 &gt;5000 
               
               
                 Value 
               
               
                 Median 
                 1.010 
                 6.4 
                 96.4 
                 124 
                 148 
                 412 
                 874 
               
               
                 Value 
               
               
                 Minimum 
                 1.002 
                 5.4 
                 22.7 
                 7 
                 8 
                 9 
                 5 
               
               
                 Value 
               
               
                   
               
            
           
         
       
     
     Example 9 
     The urine of 9 patients who were prescribed 600 mg of Seroquel® (quetiapine) was tested for compliance (Table 17). 100 μL of each patient specimen was diluted with 50 μL of 1.6 μg/mL of quetiapine-D8 (internal standard) in methanol and 350 μL of 0.1% formic acid. Samples were subsequently vortexed and centrifuged prior to the injection of 5 μL on the QQQ. 
     The preponderance of quetiapine carboxylic acid and quetiapine sulfoxide in the urine as the major metabolic urine compounds is shown in Table 17. Assuming 9 opportunities to determine the patient to be either positive or negative for Seroquel® dosing, the use of quetiapine carboxylic acid and quetiapine sulfoxide resulted in ˜100% correct identification of those taking the prescribed medicine. The data in Table 18 demonstrate the “normal” nature of the sample validity criteria (i.e., pH, specific gravity, and creatinine). Without the quetiapine carboxylic acid and quetiapine sulfoxide metabolites, ˜78% were determined to be positive solely by the parent compound quetiapine and ˜89% were determined to be positive when using the parent compound quetiapine in conjunction with 7-hydroxy quetiapine. Using all 4 analytes resulted in 100% correct identification of those taking the prescribed medicine. Thus, use of quetiapine carboxylic acid and quetiapine sulfoxide as a urine biomarker at this dose does add value to compliance monitoring for Seroquel®. 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Test Results from Patients Prescribed 600 mg/day Seroquel ® (all parent 
               
               
                 and metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
                 All 4 
               
               
                 Subject 
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
                 mets 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 LO 
                 1.007 
                 7.1 
                 104.1 
                 13 
                 59 
                 &gt;5000 
                 815 
                 + 
               
               
                 LP 
                 1.006 
                 7.5 
                 101.4 
                 288 
                 1919 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 LQ 
                 1.019 
                 5.3 
                 384.4 
                 ND 
                 ND 
                 6 
                 ND 
                 + 
               
               
                 LR 
                 1.009 
                 6.5 
                 203.6 
                 77 
                 10 
                 &gt;5000 
                 1252 
                 + 
               
               
                 LS 
                 1.010 
                 7.1 
                 215.2 
                 4999 
                 1104 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 LT 
                 1.005 
                 7.1 
                 23.0 
                 103 
                 295 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 LU 
                 1.006 
                 7.0 
                 33.9 
                 ND 
                 6 
                 377 
                 73 
                 + 
               
               
                 LV 
                 1.010 
                 6.1 
                 129.5 
                 1026 
                 214 
                 1598 
                 &gt;5000 
                 + 
               
               
                 LW 
                 1.007 
                 6.2 
                 86.7 
                 18 
                 19 
                 4050 
                 592 
                 + 
               
               
                   
               
               
                 ND: Indicates that the listed parent or metabolite compound was either not detected or detected below the established cut-off of 5 ng/mL indicating a negative result for that particular subject. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 Sample Validity and Urine Results Summary at 600 mg/day (all parent and 
               
               
                 metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
               
               
                   
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Average 
                 1.009 
                 6.7 
                 142.4 
                 932 
                 453 
                 1508 
                 683 
               
               
                 Standard 
                 0.004 
                 0.6 
                 105.4 
                 1693 
                 651 
                 1582 
                 425 
               
               
                 Deviation 
               
               
                 Maximum 
                 1.019 
                 7.5 
                 384.4 
                 4999 
                 1919 
                 &gt;5000 
                 &gt;5000 
               
               
                 Value 
               
               
                 Median 
                 1.007 
                 7.0 
                 104.1 
                 103 
                 136 
                 988 
                 704 
               
               
                 Value 
               
               
                 Minimum 
                 1.005 
                 5.3 
                 23.0 
                 13 
                 6 
                 6 
                 73 
               
               
                 Value 
               
               
                   
               
            
           
         
       
     
     Example 10 
     The urine of 4 patients who were prescribed 800 mg of Seroquel® (quetiapine) was tested for compliance (Table 19). 100 μL of each patient specimen was diluted with 50 μL of 1.6 μg/mL of quetiapine-D8 (internal standard) in methanol and 350 μL of 0.1% formic acid. Samples were subsequently vortexed and centrifuged prior to the injection of 5 μL on the QQQ. 
     The preponderance of quetiapine carboxylic acid and quetiapine sulfoxide in the urine as the major metabolic urine compounds is shown in Table 19. Assuming 4 opportunities to determine the patient to be either positive or negative for Seroquel® dosing, the use of quetiapine carboxylic acid and quetiapine sulfoxide resulted in ˜100% correct identification of those taking the prescribed medicine. The data in Table 20 demonstrate the “normal” nature of the sample validity criteria (i.e., pH, specific gravity, and creatinine). Without the quetiapine carboxylic acid and quetiapine sulfoxide metabolites, ˜75% were determined to be positive solely by the parent compound quetiapine and ˜100% were determined to be positive when using the parent compound quetiapine in conjunction with 7-hydroxy quetiapine. Using all 4 analytes resulted in 100% correct identification of those taking the prescribed medicine. 
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 Test Results from Patients Prescribed 800 mg/day Seroquel ® (all parent 
               
               
                 and metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
                 All 4 
               
               
                 Subject 
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
                 mets 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 LX 
                 1.003 
                 7.3 
                 57.3 
                 137 
                 512 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                 LY 
                 1.008 
                 6.5 
                 81.8 
                 27 
                 262 
                 &gt;5000 
                 1906 
                 + 
               
               
                 LZ 
                 1.010 
                 6.0 
                 233.1 
                 ND 
                 48 
                 52 
                 7 
                 + 
               
               
                 MA 
                 1.017 
                 5.7 
                 165.6 
                 524 
                 460 
                 &gt;5000 
                 &gt;5000 
                 + 
               
               
                   
               
               
                 ND: Indicates that the listed parent or metabolite compound was either not detected or detected below the established cut-off of 5 ng/mL indicating a negative result for that particular subject. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 Sample Validity and Urine Results Summary at 800 mg/day (all parent and 
               
               
                 metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Quetiapine 
                   
               
               
                   
                 Specific 
                   
                 Creatinine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
               
               
                   
                 Gravity 
                 pH 
                 (mg/dL) 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Average 
                 1.010 
                 6.4 
                 134.5 
                 229 
                 320 
                 52 
                 957 
               
               
                 Standard 
                 0.005 
                 0.6 
                 69.7 
                 213 
                 183 
                 0 
                 950 
               
               
                 Deviation 
               
               
                 Maximum 
                 1.017 
                 7.3 
                 233.1 
                 524 
                 512 
                 &gt;5000 
                 &gt;5000 
               
               
                 Value 
               
               
                 Median 
                 1.009 
                 6.3 
                 123.7 
                 137 
                 361 
                 52 
                 957 
               
               
                 Value 
               
               
                 Minimum 
                 1.003 
                 5.7 
                 57.3 
                 27 
                 48 
                 52 
                 7 
               
               
                 Value 
               
               
                   
               
            
           
         
       
     
     Example 11 
     The urine of 29 patients who were prescribed various doses of Seroquel® (quetiapine) was tested for compliance after enzymatic hydrolysis (Table 21). 100 μL of each patient specimen was diluted with 400 μL of a “master mix” that included 1.6 μg/mL of quetiapine-D8 (internal standard), 0.06 M phosphate buffer, and at least 1450 U of a recombinant β-glucuronidase enzyme. Samples were subsequently vortexed, incubated for 1 hr at ˜65° C., and then centrifuged prior to the injection of 5 μL on the QQQ. 
     The preponderance of quetiapine carboxylic acid and quetiapine sulfoxide post-hydrolysis in the urine as the major metabolic urine compounds is shown in Table 21. Assuming 29 opportunities to determine the patient to be either positive or negative for Seroquel® dosing, the use of quetiapine carboxylic acid and quetiapine sulfoxide resulted in ˜100% correct identification of those taking the prescribed medicine with or without enzymatic hydrolysis. The data in Table 22 demonstrate the “normal” nature of the sample validity criteria (i.e., pH, specific gravity, and creatinine). Without the quetiapine carboxylic acid and quetiapine sulfoxide metabolites, ˜69% were determined to be positive solely by the parent compound quetiapine pre-hydrolysis and ˜97% were determined to be positive solely by the parent compound quetiapine post-hydrolysis. Using quetiapine in conjunction with 7-hydroxy quetiapine 79% were determined to be positive pre-hydrolysis and ˜97% were determined to be positive post-hydrolysis. 
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 Test Results from Patients Prescribed Seroquel ® Post-Hydrolysis (all 
               
               
                 parent and metabolite data reported in ng/mL). 
               
            
           
           
               
               
               
            
               
                   
                 Pre-Hydrolysis Results 
                 Post-Hydrolysis Results 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Quetiapine 
                   
                   
                   
                 Quetiapine 
                   
               
               
                   
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
                   
                 7-Hydroxy 
                 Carboxylic 
                 Quetiapine 
               
               
                 Subject 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
                 Quetiapine 
                 Quetiapine 
                 Acid 
                 Sulfoxide 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 B 
                 ND 
                 ND 
                 9 
                 ND 
                 67 
                 7 
                 187 
                 25 
               
               
                 T 
                 ND 
                 ND 
                 6 
                 ND 
                 86 
                 7 
                 176 
                 24 
               
               
                 W 
                 ND 
                 ND 
                 5 
                 ND 
                 ND 
                 ND 
                 12 
                 ND 
               
               
                 AJ 
                 ND 
                 ND 
                 5 
                 ND 
                 29 
                 ND 
                 156 
                 24 
               
               
                 AQ 
                 1118 
                 694 
                 &gt;5000 
                 740 
                 &gt;5000 
                 1853 
                 &gt;5000 
                 863 
               
               
                 BY 
                 17 
                 51 
                 &gt;5000 
                 2143 
                 4059 
                 298 
                 &gt;5000 
                 2457 
               
               
                 CG 
                 ND 
                 357 
                 &gt;5000 
                 &gt;5000 
                 1494 
                 444 
                 &gt;5000 
                 &gt;5000 
               
               
                 CH 
                 ND 
                 258 
                 &gt;5000 
                 &gt;5000 
                 2579 
                 530 
                 &gt;5000 
                 &gt;5000 
               
               
                 ED 
                 ND 
                 ND 
                 10 
                 ND 
                 14 
                 ND 
                 76 
                 13 
               
               
                 FV 
                 208 
                 262 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 623 
                 &gt;5000 
                 &gt;5000 
               
               
                 FW 
                 315 
                 29 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 616 
                 &gt;5000 
                 &gt;5000 
               
               
                 FX 
                 97 
                 5 
                 &gt;5000 
                 2971 
                 3019 
                 78 
                 &gt;5000 
                 2505 
               
               
                 GF 
                 187 
                 262 
                 &gt;5000 
                 &gt;5000 
                 2928 
                 556 
                 &gt;5000 
                 &gt;5000 
               
               
                 GG 
                 222 
                 116 
                 &gt;5000 
                 &gt;5000 
                 1271 
                 309 
                 &gt;5000 
                 &gt;5000 
               
               
                 HQ 
                 269 
                 133 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 516 
                 &gt;5000 
                 &gt;5000 
               
               
                 HR 
                 4574 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 3588 
                 &gt;5000 
                 &gt;5000 
               
               
                 HS 
                 755 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 3588 
                 &gt;5000 
                 &gt;5000 
               
               
                 HY 
                 917 
                 1961 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 3751 
                 &gt;5000 
                 &gt;5000 
               
               
                 IF 
                 ND 
                 200 
                 &gt;5000 
                 &gt;5000 
                 2369 
                 311 
                 &gt;5000 
                 3866 
               
               
                 IH 
                 361 
                 63 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 2545 
                 &gt;5000 
                 &gt;5000 
               
               
                 IK 
                 873 
                 2034 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
               
               
                 JY 
                 77 
                 324 
                 &gt;5000 
                 4484 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
               
               
                 KG 
                 304 
                 580 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 1185 
                 &gt;5000 
                 &gt;5000 
               
               
                 KH 
                 1137 
                 958 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 3152 
                 &gt;5000 
                 &gt;5000 
               
               
                 KV 
                 120 
                 39 
                 &gt;5000 
                 &gt;5000 
                 3028 
                 3941 
                 &gt;5000 
                 &gt;5000 
               
               
                 LQ 
                 ND 
                 ND 
                 6 
                 ND 
                 15 
                 ND 
                 56 
                 8 
               
               
                 LR 
                 77 
                 10 
                 &gt;5000 
                 1252 
                 2147 
                 509 
                 &gt;5000 
                 1541 
               
               
                 LS 
                 4999 
                 1104 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 2738 
                 &gt;5000 
                 &gt;5000 
               
               
                 LX 
                 137 
                 512 
                 &gt;5000 
                 &gt;5000 
                 4911 
                 976 
                 &gt;5000 
                 &gt;5000 
               
               
                 Average 
                 838 
                 474 
                 7 
                 2318 
                 1868 
                 1397 
                 111 
                 1133 
               
               
                 Standard Deviation 
                 1362.9 
                 577.3 
                 2.0 
                 1324.8 
                 1546.1 
                 1360.2 
                 65.9 
                 1324.8 
               
               
                 Maximum Value 
                 4999 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
                 &gt;5000 
               
               
                 Median Value 
                 287 
                 262 
                 6 
                 2143 
                 2147 
                 616 
                 116 
                 444 
               
               
                 Minimum Value 
                 17 
                 5 
                 5 
                 740 
                 14 
                 7 
                 12 
                 8 
               
               
                   
               
               
                 ND: Indicates that the listed parent or metabolite compound was either not detected or detected below the established cut-off of 5 ng/mL indicating a negative result for that particular subject. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22 
               
             
            
               
                   
               
               
                 Sample Validity and Urine Results Summary for Post-Hydrolysis. 
               
            
           
           
               
               
               
               
            
               
                   
                 Specific Gravity 
                 pH 
                 Creatinine (mg/dL) 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                 Average 
                 1.013 
                 6.3 
                 165.2 
               
               
                 Standard Deviation 
                 0.005 
                 0.8 
                 86.9 
               
               
                 Maximum Value 
                 1.022 
                 8.0 
                 384.4 
               
               
                 Median Value 
                 1.013 
                 6.2 
                 139.4 
               
               
                 Minimum Value 
                 1.003 
                 4.9 
                 31.6 
               
               
                   
               
            
           
         
       
     
     From the foregoing, it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but that various modifications may be made without deviating from the scope of the invention. Accordingly, the invention is not limited except as by the appended claims.