bluuebunny/crossref_metadata_2025 huggingface dataset:
No Pharmacokinetic or Pharmacodynamic Interaction Between Theophylline and the Leukotriene Biosynthesis Inhibitor BAY x 1005
Authors: Groen Henk , Moesker Harm L. , Leeuwenkamp Oscar R. , Sollie Frans A. E. , Jonkman Jan H. G.
Published: March 2013

An open, randomized, three‐period crossover study was conducted to compare the steady‐state pharmacokinetics, pharmacodynamics, and tolerability of concomitant administration of BAY × 1005 and theophylline in 12 healthy volunteers. BAY × 1005 (250 mg twice daily; treatment A) and theophylline (400 mg twice daily; treatment B), were administered alone and concomitantly (treatment C) for 6 days with a final morning dose on day 7. The treatments were separated by washout periods of at least 5 days. Pharmacokinetic parameters were derived from concentrations of BAY × 1005 and theophylline as measured by high‐performance liquid chromatography in plasma collected before the morning dose on days 5 and 6 and at various times on day 7 of each period until 24 hours after drug administration. Adverse events, vital signs, electrocardiograms, and clinical laboratory studies were monitored as safety parameters. Levels of leukotriene B4 (LTB4) were assessed in plasma collected on days 1 and 7. The treatments were well tolerated by all participants. The ratios of maximum concentration (Cmax) and area under the concentration‐time curve for one 12‐hour dosing interval (AUC) for treatment C versus B for theophylline on day 7 was 98% for both parameters. For BAY × 1005, the ratios of treatment C versus treatment A were 94% for Cmax and 101 % for AUC. Plasma LTB4 remained virtually unchanged during either treatment. Steady‐state concentrations of theophylline were not affected by concomitant BAY × 1005 intake, and addition of theophylline had no clinically relevant effect on steady‐state plasma concentrations of BAY × 1005. The combination of theophylline and BAY × 1005 did not lead to a change in nature, intensity, or frequency of adverse events.
The Effect of Orlistat on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Volunteers
Authors: Zhi Jianguo , Melia Angela T. , Guerciolini Roberto , Koss‐Twardy Susan G. , Passe Sharon M. , Rakhit Ashok , Sadowski James A.
Published: March 2013

To assess the effect of orlistat on the pharmacokinetics and pharmacodynamics of warfarin, a third‐party blind, placebo‐controlled, randomized, two‐way crossover study was performed in 12 healthy volunteers. Each participant received single 30‐mg oral doses of racemic warfarin sodium (Coumadin; DuPont Pharma, Wilmington, DE) administered on the eleventh day of treatment with 120 mg orlistat (treatment A) and placebo (treatment B) three times a day for 16 days; the two treatments were separated by a 3‐week washout period. Serial blood samples were collected before and at appropriate intervals after each dose of warfarin to determine plasma concentrations of R‐warfarin and S‐warfarin and blood prothrombin time (PT) and plasma Factor VII concentration. In addition, serum concentrations of vitamin K1 and its epoxide and of osteocalcin and its undercarboxylated form were measured before breakfast on days −7, 1, 4, 6, and 10. Equivalent results between treatments with orlistat and placebo were found with regard to all pharmacokinetic parameters of R– and S‐warfarin (except for time to maximum concentration of R‐warfarin). Pharmacodynamic parameters of warfarin (PT and Factor VII) and vitamin K nutritional status parameters (ratios of vitamin K1 to vitamin K1 epoxide and undercarboxylated osteocalcin to osteocalcin) also were unaltered by orlistat. Orlistat administered at doses of 120 mg three times daily did not significantly alter the pharmacokinetics and pharmacodynamics of a single 30‐mg oral dose of warfarin in healthy volunteers.
Effect of a Combination of Gemfibrozil and Niacin on Lipid Levels
Authors: Spencer Gregory A. , Wirebaugh Stewart , Whitney Edwin J.
Published: March 2013

To determine the effect of the combination of niacin and gemfibrozil on the lipid profile, a retrospective review was conducted of 161 patients who were prescribed a combination of gemfibrozil and niacin for 6 to 12 months at a community‐based lipid clinic. Low‐density lipoprotein (LDL) and high‐density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, ratio of total cholesterol to HDL, alanine aminotransferase (ALT), and weight were measured at entry to the clinic, 2 months after dietary instruction, during single‐agent therapy, and during combination therapy. Mean doses of niacin and gemfibrozil were 1,229 mg/day and 1,200 mg/day, respectively. Patient weight decreased significantly after dietary instruction and after institution of combination therapy. There were no significant changes in ALT levels with either single‐agent therapy or with combination therapy. The combination of niacin and gemfibrozil produced marked and significant changes in lipid levels: total cholesterol and LDL decreased by 14%, HDL increased by 24%, the ratio of total cholesterol to HDL decreased by 30%, and triglycerides decreased by 52%. The combination of niacin and gemfibrozil in the setting of dietary instruction has a marked beneficial effect on serum lipid levels, and was most effective in patients with initial levels of HDL <40 mg/dL, triglycerides >250 mg/dL, and LDL >160 mg/dL. No episodes of ALT elevation or symptomatic myositis were seen.
Lymphocyte Responsiveness to Glucocorticoids, Cyclosporine, or Both
Authors: Briggs William A. , Gao Zu‐Hua , Gimenez Luis F. , Scheel Paul J. , Choi Michael J. , Burdick James F.
Published: March 2013

The reason why some patients with glomerular diseases respond to steroid treatment and others do not remains obscure, and it is not possible to prospectively evaluate the probability of response in individual patients. One factor that might contribute to the clinical response to treatment could be the relative sensitivity of a patient's immune system to the suppressive effects of steroids or other immunosuppressive agents. To evaluate this possibility, phytohemagglutinin (PHA)‐stimulated peripheral blood mononuclear cells (PBMC) from 16 patients with various biopsy‐proven glomerulopathies were cultured with prednisolone or methylprednisolone in final concentrations of 10−5 to 10−8 mol/L. From the dose—response curves, the concentration of steroid required to cause 50% inhibition (IC50) of the PHA‐induced proliferative response was determined. The PBMC from 10 patients also were cultured with 400 ng/mL cyclosporine both alone and with 10−7 mol/L steroid, and the inhibitory effects were calculated. There was considerable heterogeneity in the sensitivities of individual patients to steroid inhibition, and the mean ± SEM IC50 was significantly lower for methylprednisolone than for prednisolone. Cyclosporine caused 50% or greater inhibition in 6 of the 10 patients but had <10% inhibitory effect in 2 patients. In most patients studied, cyclosporine plus steroid was significantly more inhibitory than cyclosporine alone, but the combination was usually no more effective than 10−7 mol/L methylprednisolone alone. These results are consistent with the hypothesis that differences in the sensitivity of individual patients' immune systems to the immunosuppressive effects of steroids and cyclosporine might contribute to differences in their clinical responsiveness to treatment.
Pharmacokinetics of Testosterone in Hypogonadal Men After Transdermal Delivery: Influence of Dose
Authors: Brocks Dion R. , Meikle A. Wayne , Boike Steven C. , Mazer Norman A. , Zariffa Nevine , Audet Patricia R. , Jorkasky Diane K.
Published: March 2013

To assess the pharmacokinetics of testosterone after application of one, two, or three testosterone transdermal delivery systems to hypogonadal patients, 12 hypogonadal men (mean age 46.6 ± 10.5 years) were enrolled in an open‐label, randomized, crossover study. Each application period comprised 4 days: a 2‐day washout period with no exogenous testosterone therapy followed by 2 days of therapy with one, two, or three transdermal systems applied daily to the patient's back. On day 4 of each period, serial blood samples were collected for determination of total and non‐sex hormone binding globulin (non‐SHBG) bound serum testosterone concentrations. Serum concentrations of testosterone were determined using validated radioimmunoassay methods. Residual testosterone analysis of used transdermal systems was used to estimate testosterone delivery through the skin. In general, serum concentrations of testosterone rose in accordance with an increase in dose. Using a strict bioequivalence approach to dose proportionality, the increases in area under the concentration—time curve (AUC) and morning concentrations were proportional to the increase in dose from two to three transdermal systems, but somewhat less than proportional with an increase from one to two transdermal systems. Results from the non‐SHBG bound serum testosterone concentrations closely paralleled those of total serum testosterone. Use of three transdermal systems yielded serum concentrations of testosterone that tended to be above the upper limit of the normal range. The AUC and cumulative release of testosterone were linearly related to the number of applied systems. If necessary, the standard recommended dose of two testosterone transdermal delivery systems can be modified to accommodate interindividual differences in testosterone requirements of hypogonadal men.
Detection of Carbamazepine Drug Interaction by Multiple Peak Approach Screening using Routine Clinical Pharmacokinetic Data
Authors: Yukawa Eiji , Aoyama Toshinobu
Published: March 2013

Multiple peak approach screening was used to detect the effects of other antiepileptic drugs on the population estimates of relative clearance of carbamazepine. Routine clinical pharmacokinetic data (N = 1,010) collected from 466 patients receiving carbamazepine were analyzed according to a simple steady‐state pharmacokinetic model with the use of NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. NONMEM estimates indicated that carbamazepine clearance decreased nonlinearly with increasing total body weight (TBW) in the maturation process (over an age range of 5 months to 15 years) and increased nonlinearly with increasing daily dose (mg/kg) of carbamazepine. Concomitant administration of other antiepileptic drugs resulted in an increase in clearance of carbamazepine as follows: valproic acid alone (VPA), 7%; phenobarbital alone (PB), 16%; more than two antiepileptic drugs (POLY), 27%. Final regression model of relative clearance (Cl) for all data was: Cl (mL/hr/kg) = 64.9 · TBW (kg)−0.336. DOSE (mg/kg/day)0.465 1.07VPA 1.16PB 1.27POLY
Pharmacokinetics of Retinoids in Women after Meal Consumption or Vitamin A Supplementation
Authors: Chen Chao , Mistry Goutam , Jensen Bradford , Heizmann Peter , Timm Uwe , Van Brummelen Peter , Rakhit Ashok K.
Published: March 2013

These studies were conducted to evaluate the pharmacokinetics of several retinoids after meal consumption or vitamin A supplementation to establish a reference for future assessment of teratogenic risks of retinoid therapeutic agents. In the first study, 36 healthy young female volunteers consumed single meals containing vitamin A amounts ranging from 1,305 to 169,474 IU. In the second study, 24 other female volunteers took vitamin A supplements at a dose level of 5,000, 10,000, or 25,000 IU/day for 60 days. Plasma concentrations of tretinoin, isotretinoin, 4‐oxo‐tretinoin, and 4‐oxo‐isotretinoin in samples collected during the studies were analyzed using a high‐performance liquid chromatography method with ultraviolet detection. Pharmacokinetic parameters for the retinoids were calculated using model‐independent methods. Plasma concentrations of tretinoin were not altered by meal consumption or vitamin A supplementation. Plasma levels of 4‐oxo‐tretinoin were below the assay detection limit (0.3 ng/mL) in the majority of samples collected throughout the studies. Linear relationships between dose and maximum concentration (Cmax) and dose and area under the concentration—time curve (AUC) for isotretinoin and 4‐oxo‐isotretinoin were derived from data from the meal study. For the most bioavailable formulation used in the supplement study, daily ingestion of 5,000 IU of vitamin A caused increases of 141 ± 53% and 171 ± 77% from baseline in the 24‐hour AUCs of isotretinoin and 4‐oxo‐isotretinoin, respectively. Dose‐related increases in systemic exposure to retinoids were observed after ingestion of vitamin A by means of a meal or a supplement. Findings from these studies can be used as a basis for future safety evaluations of retinoid compounds.
Single‐Dose Pharmacokinetics and Effect of Food on the Bioavailability of Topiramate, A Novel Antiepileptic Drug
Authors: Doose D. R. , Walker S. A. , Gisclon L. G. , Nayak R. K.
Published: March 2013

Topiramate, a new antiepileptic drug effective in controlling partial‐onset seizures, was administered to humans for the first time as single oral doses of 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg in a phase I safety and pharmacokinetic study. Model‐independent pharmacokinetic data analysis was performed on plasma concentration and renal excretion data for topiramate. Maximum plasma concentrations (Cmax) were observed between 1.4 and 4.3 hours after administration. Mean values for plasma Cmax and area under the concentration‐time curve (AUC) increased linearly with dose; however, a greater‐than‐proportional increase in both parameters was observed, probably due to saturable binding of the drug to erythrocytes. Mean oral clearance (Cl/F) was 22.5 to 36.1 mL/min and mean volume of distribution (Vd/F) was 38.5 to 58.0 L. Approximately 50% of the dose was excreted renally and cumulative urinary excretion increased linearly and proportionally over the 200 mg to 1,200 mg dose range. Elimination half‐life (t1/2) values calculated from plasma (21.5 hrs) and urinary data (18.5 hrs) were consistent and independent of dose. Intersubject variability was low for all parameters. Renal clearance was 13.9 mL/min, suggesting that renal tubular reabsorption may be prominently involved in the renal handling of topiramate. The elimination profile of topiramate indicated that longer sampling times are necessary in future studies to more accurately determine the t1/2. Food effect studies indicated a slight reduction in the rate (∼10% decrease in mean Cmax and mean tmax ∼2 hours later) but not the extent of absorption when topiramate was given with food. Topiramate demonstrates a number of favorable pharmacokinetic features, including linear and predictable dose‐concentration relationships, excretion mainly as unchanged drug by the kidney, a dose‐independent t1/2, low intersubject variability in pharmacokinetic parameters, and lack of clinically significant effect of food on bioavailability.
Suppression of Lymphocyte Interleukin‐2 Receptor Expression by Glucocorticoids, Cyclosporine, or Both
Authors: Briggs William A. , Gao Zu‐Hua , Xing Jing‐Jing , Gimenez Luis F. , Samaniego Milagros D. , Scheel Paul J. , Choi Michael J. , Burdick James F.
Published: March 2013

Although glucocorticoids and cyclosporine are frequently used to treat patients with various types of glomerulopathy, clinical responses to treatment vary considerably. Considerable interindividual heterogeneity in the suppressive effects of glucocorticoids on lymphocyte proliferation in vitro has been previously reported, suggesting that differences in the pharmacodynamic responsiveness of the immune system to these agents might be an important determinant of how well an individual patient responds to treatment. It also has been shown that methylprednisolone is significantly more suppressive than prednisolone. To identify cellular mechanisms by which these drugs act, a study of the suppressive effects of prednisolone, methylprednisolone, and cyclosporine on lymphocyte proliferation and the expression of the cell surface receptor for interleukin‐2 (IL‐2R) was conducted using phytohemagglutin‐stimulated peripheral blood mononuclear cells (PBMCs) from 13 patients with glomerulopathy and 12 control subjects. Heterogeneity among individuals in both parameters of lymphocyte responsiveness to these drugs was again found, and the significantly greater suppressive effect of methylprednisolone was confirmed for both proliferation and IL‐2R expression in patients and control subjects. Cyclosporine alone was moderately suppressive. For most individuals, the greatest degree of suppression occurred when cells were exposed to both cyclosporine and glucocorticoid. Further studies are being conducted to determine whether pretreatment assessment of in vitro lymphocyte responsiveness has any predictive value regarding therapeutic efficacy of each drug in individual patients and to identify of those patients likely to require a more intensive or multidrug immunosuppressive regimen.
Lithium and Neuroleptics in Combination: Is There Enhancement of Neurotoxicity Leading to Permanent Sequelae?
Authors: Goldman Stephen A.
Published: March 2013

Neurotoxicity in relation to concomitant administration of lithium and neuroleptic drugs, particularly haloperidol, has been an ongoing issue. This study examined whether use of lithium with neuroleptic drugs enhances neurotoxicity leading to permanent sequelae. The Spontaneous Reporting System database of the United States Food and Drug Administration and extant literature were reviewed for spectrum cases of lithium/neuroleptic neurotoxicity. Groups taking lithium alone (Li), lithium/haloperidol (LiHal) and lithium/nonhaloperidol neuroleptics (LiNeuro), each paired for recovery and sequelae, were established for 237 cases. Statistical analyses included pairwise comparisons of lithium levels using the Wilcoxon Rank Sum procedure and logistic regression to analyze the relationship between independent variables and development of sequelae. The Li and LiNeuro groups showed significant statistical differences in median lithium levels between recovery and sequelae pairs, whereas the LiHal pair did not differ significantly. Lithium level was associated with sequelae development overall and within the Li and LiNeuro groups; no such association was evident in the LiHal group. On multivariable logistic regression analysis, lithium level and taking lithium/haloperidol were significant factors in the development of sequelae, with multiple possibly confounding factors (e.g., age, sex) not statistically significant. Multivariable logistic regression analyses with neuroleptic dose as five discrete dose ranges or actual dose did not show an association between development of sequelae and dose. Database limitations notwithstanding, the lack of apparent impact of serum lithium level on the development of sequelae in patients treated with haloperidol contrasts notably with results in the Li and LiNeuro groups. These findings may suggest a possible effect of pharmacodynamic factors in lithium/neuroleptic combination therapy.
Effect of Grapefruit Juice on the Pharmacokinetics and Pharmacodynamics of Quinidine in Healthy Volunteers
Authors: Min David I. , Ku Yi‐Min , Geraets Douglas R. , Lee Hon‐chi
Published: March 2013

A study was conducted to examine the effect of grapefruit juice on the disposition of quinidine sulfate and changes of QT intervals after oral administration to twelve healthy male volunteers. Participants received two oral doses of quinidine sulfate tablets (400 mg) with 240 mL of water or grapefruit juice, each separated by a 1‐week washout period. Plasma samples for analysis of quinidine and its major metabolite, 3‐hydroxyquinidine, were collected for a 24‐hour period and analyzed by a high‐performance liquid chromatography method. For pharmacodynamic data, the electrocardiograms (ECGs) were performed for 12 hours, and the recordings were marked for ECG interval at all blood collection time periods. There was no significant difference in pharmacokinetic parameters of quinidine when administered with grapefruit juice or water, except for time to maximum concentration (tmax), which was 1.6 hours after administration with water and 3.3 hours after administration with grapefruit juice. Administration with grapefruit juice also resulted in a 33% decrease in the area under the concentration‐time curve (AUC) of 3‐hydroxyquinidine compared with water, but did not increase the AUC of quinidine or change the ratio of AUC of 3‐hydroxyquinidine to the AUC of quinidine. Pharmacodynamic parameters, including changes in the rate‐corrected QT (QTc) interval, closely paralleled the pharmacokinetic data, in that administration with grapefruit juice led to delayed maximal effect on QTc and reduction in maximal effect. Administration with grapefruit juice therefore delays the absorption of quinidine and inhibits the metabolism of quinidine to 3‐hydroxyquinidine.
Stereoselective Inhibition of Inducible Cyclooxygenase by Chiral Nonsteroidal Antiinflammatory Drugs
Authors: Carabaza Assumpta , Cabré Francesc , Rotllan Elisabet , Gómez Manel , Gutiérrez Marta , García M. Lluïsa , Mauleón David
Published: March 2013

The stereoselective inhibition of inducible cyclooxygenase (COX‐2) by chiral nonsteroidal antiinflammatory drugs (NSAIDs)—ketoprofen, flurbiprofen, and ketorolac—has been investigated. The activity and inhibition of COX‐2 was assessed in three different in vitro systems: guinea pig whole blood, lipopolysaccharide (LPS)‐stimulated human monocytes, and purified preparations of COX‐2 from sheep placenta. The results were compared with the inhibition of constitutive cyclooxygenase (COX‐1) in three parallel in vitro models: clotting guinea pig blood, human polymorphonuclear leukocytes, and purified COX‐1 from ram seminal vesicles. In the whole blood model, both isoenzymes were inhibited by S‐enantiomers with equal potency but S‐ketoprofen was the most active on COX‐2 (IC50 = 0.024 μmol/L). In contrast, both isoenzymes were inhibited less than 40% by all three R‐enantiomers at high concentration (>1 μmol/L). The inhibition of COX by the R‐enantiomers may be attributed to contamination with the S‐enantiomers (approximately 0.5%). A significant degree of enantioselectivity in COX‐2 inhibition was also observed in intact cells. The S‐enantiomers inhibited COX‐2 from monocytes with IC50 values in the range of 2 to 25 nmol/L, being 100 to 500‐fold more potent than the corresponding R‐enantiomers. Finally, S‐ketoprofen inhibited COX‐2 from sheep placenta (IC50 = 5.3 μmol/L) with slightly less potency than S‐ketorolac (IC50 = 0.9 μmol/L) and S‐flurbiprofen (IC50 = 0.48 μmol/L), whereas the R‐enantiomers were found to be essentially inactive (IC50 ≥ 80 μmol/L). It is concluded that the chiral NSAIDs studied here inhibit with comparable stereoselectivity both COX‐2 and COX‐1 isoenzymes, and that the inhibition of COX‐2 previously observed for racemic NSAIDs should be attributed almost exclusively to their S‐enantiomers.
Human Plasma Concentrations of R, S, and Racemic Flurbiprofen Given as a Toothpaste
Authors: Forland Steven C. , Wechter William J. , Witchwoot Sooky , Clifford Kay H. , Arnett R. Leslie , Cutler Ralph E.
Published: March 2013

Flurbiprofen, an arylpropionic acid (APA) class nonsteroidal antiinflammatory drug (NSAID), is commercially available only as the racemic mixture, although its pharmacologic effect has been credited primarily to the S isomer. In humans, the bioavailability of racemic flurbiprofen absorbed from the oral cavity has been studied measuring the total concentration of S‐ and R‐flurbiprofen, and the pharmacokinetics of S‐ and R‐flurbiprofen have been studied after oral administration of racemic flurbiprofen. In this study, the plasma concentrations of S‐flurbiprofen and to some extent R‐flurbiprofen were studied after brushing with a toothpaste containing different mixtures of S‐ and R‐flurbiprofen. The toothpaste formulations contained 1% racemic (50:50), eutectic (14:86), 1%, 0.5%, and 0.25% (5:95) R‐ to S‐flurbiprofen. Both S‐ and R‐flurbiprofen were rapidly absorbed, with a time to reach maximum concentration (tmax) of 1.2 to 1.4 hours. Based on the AUC, the amount of S‐flurbiprofen absorbed increased proportionally when given as the 0.25% (5:95) preparation to the 0.5% (5:95) mixture but did not increase significantly above the 0.5% (5:95) mixture when given as 1% (5:95) R‐ to S‐flurbiprofen. This suggests that dose‐proportional absorption of S‐flurbiprofen is not maintained at higher concentrations. The elimination of S‐flurbiprofen appears to be variable and prolonged after this mode of administration, as observed from plasma concentrations. Further controlled and more prolonged studies of S‐ and R‐flurbiprofen are needed to confirm these observations.
Tolerance And Efficacy of Polyethylene Glycol 3350/Electrolyte Solution Versus Lactulose In Relieving Opiate Induced Constipation: A Double‐Blinded Placebo‐Controlled Trial
Authors: Freedman Michael D. , Schwartz H. Jeffrey , Roby Robert , Fleisher Steven
Published: March 2013

Chronicity and high therapeutic cost prompted this study to determine a cost‐effective and efficacious regimen in treating narcotic‐induced constipation. The efficacy of lactulose was compared with polyethylene glycol 3350/electrolyte solution for relief of methadone‐induced constipation. This was a randomized, triple cross‐over after control run‐in (no treatment) study conducted at a methadone maintenance program in Baltimore, Maryland in 57 patients who are affected by opiate‐induced constipation. The study was measured by self‐reported frequencies, consistency, and ease of defecation during a 1 week run‐in control period, followed by 3 treatment phases of 2 weeks each. Polyethylene glycol 3350/electrolyte solution and lactulose produced more “nonhard” stools than the placebo (P<0.01) and control (P<0.003). Polyethylene glycol 3350/electrolyte solution produced the loosest stool (P<0.0001) compared with the control, whereas lactulose had the most adverse effects. There were no significant differences in reducing hard stool formation in either experimental group, but both were better than having nothing or just the placebo. Polyethylene glycol/electrolyte solution resulted in the loosest (diarrheal) stool. It is also likely that polyethylene glycol/electrolyte solution is the most cost effective. J Clin Pharmacol 1997;37:904–907.
A Simplified Account of Drug Accumulation and Steady‐State Dose Equivalences
Authors: Swartz Conrad M.
Published: March 2013

The accumulation of medication taken regularly can influence its clinical effects, cumulative toxicities and steady‐state equivalent doses to similar agents, and the elimination of concurrent medications. A basic expression of drug accumulation, the Unit Dose Accumulation Ratio (UDAR), is defined as the ratio of the day‐average blood drug concentration at steady‐state to the peak blood drug concentration after one dose. In a single‐compartment analysis the UDAR is found to equal 0.0601 multiplied by the elimination half‐life (in hours). The UDARs estimated in this way approximate those found from measurements of valproic acid, desipramine, and reboxetine. Further modeling reveals that in common situations graduality of release has only small effects on UDARs. Extension to multiexponential elimination is described by simple expressions in terms of ratios of kinetic coefficients. Modeling of accumulation with biexponential elimination is depicted on a graph.

Several applications of the UDAR are illustrated. The UDAR permits determination of steady‐state dose equivalences from single dose equivalences and vice‐versa. This facilitates medication interchange, as in clinical withdrawal management by replacement of short‐acting sedative‐hypnotics with long‐acting agents, e.g., alprazolam with clonazepam. The UDAR reflects tolerance, e.g., if 30‐mg flurazepam equals 4‐mg lorazepam, the UDAR indicates that at steady‐state, 30 mg/day of flurazepam approximates 21 mg/day of lorazepam. The UDAR can estimate total exposure, e.g., to organic chlorine. The UDAR complements methods described previously for drug dose prediction and blood drug level monitoring that were simplified by expressing blood levels as averages over the day. J Clin Pharmacol 1997;37:962–970.
Pharmacokinetic and Pharmacodynamic Evaluation of the Potential Drug Interaction Between Venlafaxine and Ethanol
Authors: Troy Steven M. , Turner Mary Beth , Unruh Mary , Parker Vernon D. , Chiang Soong T.
Published: March 2013

Venlafaxine is a new antidepressant with a unique mode of action. Because many patients taking antidepressant therapy may self‐medicate with ethanol, this study was undertaken to assess the possible pharmacokinetic and pharmacodynamic interactions between venlafaxine and ethanol. This randomized, double‐blind, placebo‐controlled, two‐period crossover study was conducted with 16 healthy men. Multiple doses of venlafaxine (50 mg every 8 hours) or placebo were administered for 7 days. On days 5 and 7 a single dose of 0.5 g/kg of ethanol or a placebo solution was administered in a randomized fashion. Pharmacokinetic data indicated that ethanol administration did not affect the disposition of venlafaxine or O‐desmethylvenlafaxine. Similarly, venlafaxine administration did not affect the pharmacokinetic disposition of ethanol. Ethanol produced its expected effects on the eight psychometric tests administered. Venlafaxine produced small effects on the results of the Digit Symbol Substitution Test, the Divided Attention Reaction Time, and the Profile of Mood States. No pharmacodynamic interaction was detected between venlafaxine and ethanol.
Phase I Safety and Pharmacokinetic Studies of Brequinar Sodium after Single Ascending Oral Doses in Stable Renal, Hepatic, and Cardiac Allograft Recipients
Authors: Joshi Amita S. , King Shang‐Ying P. , Zajac Barbara A. , Makowka Leonard , Sher Linda S. , Kahan Barry D. , Menkis Alan H. , Stiller Calvin R. , Schaefle Brigitte , Kornhauser David M.
Published: March 2013

Brequinar sodium (BQR), a substituted 4‐quinoline carboxylic acid, was in clinical development in combination with cyclosporine (CsA) as a potentially effective therapy for the treatment and prophylaxis of rejection in organ transplant patients. This phase I study was performed in stable renal, hepatic, and cardiac transplant patients receiving CsA and prednisone maintenance therapy for immunosuppression. The pharmacokinetic objectives of this study were to characterize the pharmacokinetics of (a) single oral 0.5‐ to 4‐mg/kg doses of BQR when given in combination with CsA and prednisone to stable renal, hepatic, and cardiac transplant patients and (b) steady‐state oral doses of CsA, with and without single oral doses of BQR. In all three patient populations, the pharmacokinetics of BQR were characterized by a lower oral clearance (12–19 mL/min) than that seen in previous studies in patients with cancer (∼30 mL/min at similar doses) and a long terminal half life (13–18 hrs). This slower oral clearance for BQR could be due either to a drug interaction between BQR and CsA or to altered clearance or metabolic processes in patients with transplants. Steady‐state CsA trough levels and the oral clearance of CsA were not affected by BQR coadministration. Among the three transplant populations, the cardiac transplant patients had lower oral clearance values of BQR and of CsA. The cause of this lower clearance is not known. Safety results indicate that BQR was well tolerated by this patient population.
Effect of Cisapride, a Serotonin‐4 Receptor Agonist, on Aldosterone Secretion: Absence of Age‐Related Change
Authors: Huang Yu‐Yao , Hsu Brend Ray‐Sea , Tsai Jir‐Shiong
Published: March 2013

Twenty healthy volunteers (age ranging from 19 to 72) were studied for their aldosterone response to oral administration of 10 mg cisapride, a serotonin‐4 receptor agonist. The participants were studied after minimum of 4‐hour ambulation (high basal renin) and a repeated test after overnight bed rest (low basal renin). Oral administration of cisapride caused a two‐fold increase in the plasma aldosterone levels (182.6 ± 28.0% in high renin state and 203.4 ± 38.6% in low renin state; P = 0.659 between the means of two states) without affecting the plasma renin levels. Scatterplot of percentile aldosterone increment against age distribution demonstrated that the R‐square were very low (0.039 for high renin and 0.009 for low renin state). Our data suggest that the age does not alter the serotonergic mediated effect on aldosterone secretion. The cisapride effect is also independent of the different basal renin states. Cisapride, as a single oral dose, could serve as a simple test to assess the functional capacity of aldosterone secretion.
Pharmacokinetics of Dichloroacetate in Adult Patients with Lactic Acidosis
Authors: Henderson George N. , Curry Stephen H. , Derendorf Hartmut , Wright Elizabeth C. , Stacpoole Peter W.
Published: March 2013

The pharmacokinetic properties of the lactate‐lowering drug dichloroacetate were investigated in 111 adult patients with lactic acidosis who were randomized to receive dichloroacetate as part of a placebo‐controlled clinical trial. The clinical symptoms and etiology of lactic acidosis varied markedly among patients. Dichloroacetate, at a dose of 50 mg per kilogram of body weight, was administered in a 30‐minute intravenous infusion into a peripheral vein. A second dose, identical to the first, was administered 2 hours after beginning the first infusion. Plasma levels of dichloroacetate were determined from blood samples collected periodically up to 288 hours after administration and the data were subjected to pharmacokinetic modeling. The pharmacokinetic properties of dichloroacetate in these acutely ill patients were complex and differed markedly from those in healthy volunteers, whose data fitted a one‐compartment pharmacokinetic model. In contrast, the data from patients fitted one‐, two‐, or three‐compartment pharmacokinetic models or even none of these, depending on the individual. Drug clearance in plasma tended to decrease as the number of compartments required to fit the data increased or as the number of drug treatments increased.
Pharmacokinetics of Nicotine Tartrate after Single‐Dose Liquid Enema, Oral, and Intravenous Administration
Authors: Zins Bradley J. , Sandborn William J. , Mays Dennis C. , Lawson George M. , McKinney Jeffrey A. , Tremaine William J. , Mahoney Douglas W. , Zinsmeister Alan R. , Hurt Richard D. , Offord Kenneth P. , Lipsky James J.
Published: March 2013

Ulcerative colitis is predominantly a disease of nonsmokers, and transdermal nicotine is therapeutic but often results in adverse reactions. Colonic administration of nicotine tartrate as a liquid enema could decrease systemic nicotine absorption and adverse reactions. The purpose of the current study was to determine the bioavailability and pharmacokinetic parameters of nicotine after administration by hydrophilic liquid enema (acidic and basic), hydrophobic liquid enema (acidic and basic), and by oral and intravenous routes. Thirty healthy volunteers received 45 μg nicotine base/kg (as nicotine tartrate) in one of five formulations (each n = 6): hydrophilic acidic liquid enema, hydrophilic basic liquid enema, hydrophobic acidic liquid enema, hydrophobic basic liquid enema, and oral solution. All participants also received 15 μg nicotine base/kg (as nicotine tartrate) intravenously during a separate study period. Serum concentrations of nicotine were determined by gas chromatography with mass spectrometry. The mean (± SD) bioavailabilities of nicotine after administration in the liquid enema formulations (hydrophilic acidic 17 ± 18%, hydrophilic basic 16 ± 16%, hydrophobic acidic 25 ± 17%, hydrophobic basic 15 ± 12%) were similar to the bioavailability of nicotine after administration by oral solution (20 ± 25%). The bioavailabilities of nicotine for all five nonintravenous formulations were significantly less than for intravenous nicotine (100%). Serum concentrations of nicotine did not predict adverse reactions. Nicotine tartrate administered as either a liquid enema or as an oral solution had low bioavailability and was well tolerated. The therapeutic potential of nicotine tartrate liquid enemas, which can potentially limit toxicity by local (colonic) delivery of high doses of nicotine should be investigated in patients with left‐sided ulcerative colitis.
Development and Evaluation of a Clinical Psychopharmacology Educational Curriculum
Authors: Naranjo Claudio A. , Shulman Richard W. , Özdemir Vural
Published: March 2013

Clinical psychopharmacology training at the University of Toronto (Toronto, Ontario, Canada) was in need of improvement. The authors developed and evaluated a Clinical Psychopharmacology Educational Curriculum to complement the education provided to trainees and staff. The program consisted of journal clubs, case rounds, and didactic research tutorials and lectures. The program was attended by staff, fellows, psychiatry residents, graduate pharmacology students, medical students, and pharmacists. No course credit or continuing medical education credits were offered for participating in the program. The program ran for two academic years (September 1994‐June 1996). Anonymous evaluation forms were collected after the sessions. These evaluated content, presentation style, and educational value, each on a scale from 1 (unsatisfactory) to 5 (excellent). Ratings for each component of the curriculum were close to excellent. The case rounds were rated slightly better for presentation style and educational value. Positive ratings suggest that similar efforts, particularly using case‐based methods, should be developed in other teaching hospitals contingent on availability of qualified faculty and funding.
Intention‐to‐Treat Analysis in Randomized Trials: Who Gets Counted?
Authors: Gibaldi Milo , Sullivan Sean
Published: March 2013

This article discusses the rationale and implications associated with the selection and use of analysis strategies for randomized clinical trials as they relate to protocol deviations. The topics addressed specifically are the conceptual and methodologic approaches and biases of clinical efficacy and effectiveness assessment. Examples are provided that highlight the consequences of different analytic strategies, particularly regarding intention‐to‐treat analysis. Favored by statisticians, intention‐to‐treat analysis seeks to answer the question, “Is it better to adopt a policy of treatment A if possible, with deviations if necessary, or a policy of treatment B if possible, with deviations if necessary?” This is a relevant question, sometimes more relevant than “Is treatment A better than treatment B?” The authors suggest that different analytic strategies may be more or less appropriate depending on the intended audience.
Antagonism of Warfarin‐Induced Hypoprothrombinemia with Use of Low‐Dose Subcutaneous Vitamin K1
Authors: Fetrow C. W. , Overlock Timothy , Leff Louis
Published: March 2013

Historically, oral or intravenous doses of vitamin K1 for supratherapeutic anticoagulation have ranged from 10 mg to 50 mg. Intravenous administration of vitamin K1 carries a rare but serious risk. No data specifically confirm the use of low‐dose subcutaneous vitamin K1 for warfarin induced hypoprothrombinemia. The aim of this study was twofold: 1) to test the general utility of recommendations put forth by the Third Conference of Antithrombotic Therapy, and 2) to test the reliability of the subcutaneous route for this treatment. Six patients with excessive international normalized ratios (INRs) and no intervention were compared with 12 patients with excessive INRs who were given low doses of subcutaneous vitamin K1. The rate of decline of the INR to 3 was statistically significantly greater in favor of the treatment group. The amount of time required to achieve an INR of 3 differed between the two groups by almost 1 complete day (23 hours) in favor of the treatment group. The average dose of subcutaneous vitamin K1 required to return a patient to an INR of 3 or less was 4.9 mg. A few participants required an additional dose of the same magnitude or less to return to an INR within the therapeutic range. This study provides sufficient evidence that subcutaneous vitamin K1 is an effective alternative to intravenous administration of vitamin K1 for warfarin‐induced hypoprothrombinemia and permits administration in accordance with the current published recommendations for intravenous vitamin K1 administration in this scenario.
Population‐Based Investigation of Relative Clearance of Digoxin in Japanese Patients by Multiple Trough Screen Analysis: An Update
Authors: Yukawa Eiji , Honda Tomoo , Ohdo Shigehiro , Higuchi Shun , Aoyama Toshinobu
Published: March 2013

The steady‐state concentrations of digoxin at trough levels were studied to reestablish the role of patient characteristics in estimating doses for digoxin using routine therapeutic drug‐monitoring data. The data (n = 548) showing steady‐state serum concentrations of digoxin after repetitive oral administration in 385 hospitalized patients were analyzed using NONMEM, a computer program designed to analyze pharmacokinetics in study populations by allowing pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished with a simple steady‐state pharmacokinetic model. The effect of a variety of developmental and demographic factors on the clearance of digoxin was investigated. Estimates generated by NONMEM indicated that clearance of digoxin was influenced by the demographic variables of age, total body weight, serum creatinine, estimated creatinine clearance, gender, the coadministration of spironolactone, the presence or absence of congestive heart failure, and the administration of a half‐tablet. The interindividual variability in the clearance of digoxin was modeled with proportional error with an estimated coefficient of variation of ∼22%; the residual variability was ∼25.0%. An a priori method, based on the value for clearance of digoxin obtained by NONMEM analysis, was proposed as a useful adjunct for the prediction of the steady‐state concentration of digoxin at trough level as a function of the maintenance dose of digoxin.
Pharmacokinetics and Effect of Ticlopidine on Platelet Aggregation in Subjects with Normal and Impaired Renal Function
Authors: Buur Tom , Larsson Rutger , Berglund Ulf , Donat Francois , Tronquet Claude
Published: March 2013

The pharmacokinetics and the effect of ticlopidine on platelet aggregation were determined in patients with chronic renal failure (n = 6), who were not on dialysis and had glomerular filtration of 16.9 ± 4.4 mL/min, and were matched with the pharmacokinetics and effects in healthy volunteers (n = 7). Participants were studied after acute oral administration of ticlopidine at the beginning of the study and after 36 days of treatment with 250 mg twice daily. For unchanged ticlopidine there were no significant differences between the concentration profiles for the two study groups. By day 36 the minimum concentrations in plasma were identical (0.35 ± 0.22 mg/L and 0.36 ± 0.21 mg/L, respectively). Using 14C‐labeled ticlopidine, the concentration profiles of radioactivity on day 1 were similar to those on day 36 for both groups. However, maximum concentrations and area under the concentration—time curve at 72 hours were both higher in patients with renal failure than in healthy volunteers. Treatment with ticlopidine progressively decreased sensitivity to adenosine diphosphate—induced platelet aggregation. At day 36, the concentration of adenosine diphosphate required to achieve 50% platelet aggregation was approximately 2.5 times greater than before treatment. Both patients and healthy volunteers exhibited closely comparable changes. The response to collagen induced platelet aggregation was not changed in patients by treatment with ticlopidine. In contrast, volunteers required a three‐ to fourfold increase in collagen concentration to achieve 50% platelet aggregation after 36 days of therapy. Although some differences in both pharmacokinetics and pharmacodynamics of ticlopidine have been demonstrated between patients and and healthy volunteers, results in this study demonstrated that a change of dosage is not required in renal failure.
Pharmacokinetics and Cardiovascular Effects of Ma‐Huang (Ephedra sinica) in Normotensive Adults
Authors: White Laura M. , Gardner Stephanie F. , Gurley Bill J. , Marx Michael A. , Wang Pei‐Ling , Estes Mark
Published: March 2013

The purpose of this study was to evaluate heart rate and blood pressure responses to a commercially available source of ma‐haung, a natural source of the sympathomimetic substance, ephedrine, and to evaluate the pharmacokinetic properties of the product in normotensive, healthy adults. On day 1, twelve study participants were monitored with an ambulatory blood pressure device between hours 7 and 20. On day 2, they ingested four capsules of powdered ma‐huang at hours 8 and 17 while again wearing the monitor between hours 7 and 20. Serial plasma samples were obtained and concentrations of ephedrine were analyzed by high‐performance liquid chromatography. Pharmacokinetic parameters of ephedrine were determined from plasma concentration‐time profiles. The ephedrine alkaloid content of each capsule was also determined by high‐performance liquid chromatography. Six participants experienced a statistically significant increase in heart rate, but the effects on blood pressure were variable. The half‐life, volume of distribution, clearance, and maximum concentration in plasma of ephedrine in the ma‐huang product were similar to values previously reported for a 20‐mg, immediate‐release ephedrine tablet. Values for the absorption rate were considerably lower and time to reach maximum concentration was longer for the capsules, compared with the standard tablet. Variability in alkaloid content of ephedrine was low and yielded a mean dose of ephedrine at 19.4 mg; pseudoephedrine at 4.9 mg; and methylephedrine at 1.2 mg for a four‐capsule dose. In summary, ma‐haung had variable effects on blood pressure and increased heart rate in healthy, normotensive adults. Pharmacokinetic parameters for ephedrine were in agreement with those previously reported; however, the absorption rate was much slower after ingestion of ma‐huang.
Initial Pharmacokinetics and Bioavailability of PSC 833, a P‐Glycoprotein Antagonist
Authors: Lush Richard M. , Meadows Beverly , Fojo Antonio T. , Kalafsky Gaetana , Smith Harold T. , Bates Susan , Figg William D.
Published: March 2013

Resistant cancer cells have been shown to overexpress a 170‐kd membrane glycoprotein called P‐glycoprotein. P‐glycoprotein, a product of the multidrug resistance 1 gene, functions as an energy‐dependent efflux pump that decreases intracellular drug concentrations. A variety of nonchemotherapeutic agents have been shown to inhibit P‐glycoprotein—dependent drug efflux including cyclosporin. PSC 833 is a nonimmunosuppressive derivative of cyclosporin D with the ability to reverse multidrug resistance because of P‐glycoprotein overexpression in vitro. As part of early clinical development of PSC 833, the authors investigated the bioavailability of an oral formulation of PCS 833. PSC 833 (3 mg/kg) was administered as a 2‐hour intravenous infusion on day 1 of the treatment cycle. Serial blood samples for the determination of PSC 833 whole blood concentrations were obtained after both the intravenous and oral doses. On day 5 of the study, patients received a single oral dose (9 mg/kg) of PSC 833. A total of 14 patients were treated. The intravenous data were best described by a two‐compartment open model. The oral data also were described using a two‐compartment model, with oral absorption incorporating a lag time to account for possible delays in absorption. There was large intra‐ and interpatient variability in the pharmacokinetics of PSC 833 in these patients. The absolute bioavailability of PSC 833 was 34% but ranged from 3% to 58% of the administered dose. The clearance (Cl) of PSC 833, in general, was consistent between the two dose forms administered. The pharmacokinetic behavior of PSC 833 appears to be similar to that of cyclosporine.