bluuebunny/crossref_metadata_2025 huggingface dataset:
A Double‐Blind, Placebo‐Controlled Evaluation of the Effect of Oral Doses of Rizatriptan 10 mg on Oral Contraceptive Pharmacokinetics in Healthy Female Volunteers
Authors: Shadle Craig R. , Liu Guanghan , Goldberg Michael R.
Published: July 2003

Rizatriptan (MAXALT™), a potent, oral 5‐HT1B/1D agonist with a rapid onset of action, is available now for the acute treatment of migraine. This study examined the pharmacokinetic and clinical interaction between rizatriptan 10 mg and the components (ethinyl estradiol [EE] 35 μg and norethindrone [NET] 1.0 mg) of a well‐established oral contraceptive combination product, ORTHO‐NOVUM 1/35. Levels of sex hormone binding globulin (SHRG), a protein increased by EE to which NET binds, were also examined. In this two‐period crossover study, 20 healthy young female subjects received a coadministration of 8 days of rizatriptan treatment (6 days of single‐dose 10 mg rizatriptan and 2 days of multiple‐dose rizatriptan, 10 mg q 4 hours for three doses, giving a total daily dose of 30 mg on Days 7 and 8) or matching placebo along with their daily dose (one tablet) of ORTHO‐NOVUM 1/35 within their oral contraceptive cycle. Plasma was sampled for EE, NET, and SHBG concentrations. Safety evaluations included routine laboratory safety studies, physical examinations, and monitoring for ECG, vital signs, and adverse events. There were no statistically significant differences in any of the pharmacokinetic parameters of EE or NET between the rizatriptan and placebo treatment periods, thus indicating that rizatriptan had no meaningful effect on the disposition of either the EE or the NET component of ORTHO‐NOVUM 1/35. The SHBG concentration did not change throughout the entire study. Clinically, coadministration of rizatriptan with ORTHO‐NOVUM 1/35 was well tolerated. Blood pressure, heart rate, and temperature showed no consistent trend or clinically important changes. Adverse events following coadministration of rizatriptan with ORTHO‐NOVUM 1/35 were similar to those reported when placebo was given with ORTHO‐NOVUM 1/35. The findings of this study indicate that there is little potential for dosages as high as 30 mg/day, the maximum recommended dosing schedule, of rizatriptan to alter the plasma concentrations of oral contraceptives.
Lack of a Clinically Significant Pharmacokinetic Interaction between Fenofibrate and Pravastatin in Healthy Volunteers
Authors: Pan Wei‐Jian , Gustavson Linda E. , Achari Ramanuj , Rieser Matthew J. , Ye Xin , Gutterman Cory , Wallin Bruce A.
Published: July 2003

This study was conducted to evaluate the potential pharmacokinetic interaction between fenofibrate and pravastatin. A total of 23 healthy adult volunteers received single‐dose 201 mg fenofibrate alone, 201 mg fenofibrate + 40 mg pravastatin, and 40 mg pravastatin alone in a three‐period crossover experiment. Plasma samples were collected at predetermined times and were analyzed with validated methods for the quantitation of fenofibric acid, pravastatin, and 3α‐hydroxy‐iso‐pravastatin (3α‐iso‐PV). Pharmacokinetic parameters of these three compounds were calculated using noncompartmental methods and compared by analyses of variance and bioavailability assessments. Concomitant administration of fenofibrate and pravastatin did not affect the pharmacokinetics of either fenofibric acid or pravastatin. However, the AUC0‐∞ and Cmax of 3α‐iso‐PV were increased by 26% and 29%, respectively. The moderate increase in the formation of this pravastatin metabolite should not raise any clinical concerns due to its much lower pharmacological potency compared to pravastatin and lack of toxicity.
Gender‐Specific Effects on Verapamil Pharmacokinetics and Pharmacodynamics in Humans
Authors: Krecic‐Shepard Mary Ellen , Barnas Crissy R. , Slimko Jill , Jones Michael P. , Schwartz Janice B.
Published: July 2003

Pharmacokinetic studies of i.v. and oral racemic verapamil and 14C‐erythromycin breath tests (ERBT) were performed in 84 healthy men (n = 42) and women (n = 42). Verapamil was measured by HPLC, concentration versus time data were analyzed by noncompartmental models, protein binding was measured by equilibrium dialysis, and statistical analyses were performed by ANOVA. Clearance of i.v. and p.o. verapamil was 13.7 ± 4.3 and 58.4 ± 35 ml/min/kg (mean ± SD) in women compared to 12.6 ± 3.4 and 82.6 ± 70 ml/min/kg in men (p = 0.076). Bioavailability was higher in women (0.25 ± 0.09) compared to men (0.20 ± 0.09, p = 0.019) with a significant Gender × Formulation interaction (p = 0.04). ERBT were higher in women (p < 0.0001). Verapamil (i.v. and p.o.) decreased blood pressure in all subjects with greater heart rate increases after p.o. verapamil in women compared to men (p = 0.041). The findings suggest that sex‐specific differences in drug metabolism may occur in both the gut and the liver and involve multiple metabolic pathways and that pharmacokinetic differences will alter pharmacodynamic responses.
A Pharmacokinetic and Pharmacodynamic Study of the Potential Drug Interaction between Tasosartan and Atenolol in Patients with Stage 1 and 2 Essential Hypertension
Authors: Andrawis Nabil S. , Battle Michele M. , Klamerus Karen J. , Burghart Peter H. , Neefe Lynne , Weinryb Ira , Mayer Philip , Abernethy Darrell B.
Published: July 2003

The primary objective of this study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of tasosartan and atenolol administered alone and concomitantly under steady‐state conditions in 17 patients ages 18 to 65 years diagnosed with stage 1 to 2 essential hypertension. After a 3‐ to 14‐day qualification period, all patients received placebo tasosartan on days − 1 through 5 and 25 through 34, atenolol alone (50 mg) on days 1 through 5, atenolol (50 mg) + tasosartan (50 mg) on days 6 through 19, and tasosartan (50 mg) alone on days 20 through 24. A PK and PD evaluation of atenolol alone was performed on study day 5. On study day 19, PK and PD of both tasosartan and atenolol were assessed. PK and PD evaluation for tasosartan alone was assessed on study day 24. The coadministration of atenolol + tasosartan did not affect the pharmacokinetics of tasosartan, its major metabolite (enoltasosartan), or atenolol when compared with tasosartan or atenolol administered separately For area under the change in diastolic blood pressure curve, the reduction was significantly greater after tasosartan + atenolol compared with that after atenolol alone (336 ± 85 and 190 ± 71 mmHg • 24 h; p < 0.05 for combination and atenolol alone, respectively; mean ± SEM). Combination therapy also caused a maximal reduction in diastolic blood pressure that is significantly more than with monotherapy with atenolol (−27 ± 2 mmHg and −20 ± 2 mmHg, respectively, p < 0.05). The additive effects of tasosartan and atenolol in decreasing diastolic blood pressure may provide a rationale for combination antihypertensive therapy.
A Population Pharmacokinetic Analysis of Zanamivir in Subjects with Experimental and Naturally Occurring Influenza: Effects of Formulation and Route of Administration
Authors: Peng Amy W. , Hussey Elizabeth K. , Moore Katy H. P.
Published: July 2003

The pharmacokinetics of zanamivir were evaluated in subjects from three phase I single‐center and two phase II multicenter, randomized, double‐blind, multidose, placebo‐controlled trials. A total of 96 phase I subjects received zanamivir (3.6 to 16 mg) intranasally two or six times daily for 4 to 5 days beginning 4 hours before or 1 to 2 days after inoculation with influenza virus. A total of 75 phase II subjects with influenza or a history of exposure to naturally occurring influenza virus were administered zanamivir as an intranasal spray (3.4 mg/nostril), inhaled powder (10 mg), or combination of intranasal and inhaled formulations twice daily for 5 days. Population parameters (including demographic factors, zanamivir formulation, infection‐related variables, and concurrent medication use) were estimated by a nonlinear mixed‐effect modeling software program (NONMEM) using a one‐compartment model with first‐order absorption and conditional estimation algorithm. Formulation and route of administration were the most significant factors affecting the pharmacokinetics of zanamivir. Relative bioavailability of the inhaled powder to the intranasal drops and spray was 2.3 and 1.6, respectively. No significant differences in pharmacokinetic parameters were observed when demographic variables, indices of infection, or concurrent medication use were considered in either phase I or phase II population analyses.
Pharmacokinetics of Diclofenac Sodium in Chronic Active Hepatitis and Alcoholic Cirrhosis
Authors: Lill Jennifer S. , O'Sullivan Teresa , Bauer Larry A. , Horn John H. , Carithers Robert , Strandness D. Eugene , Lau Henry , Chan Keith , Thakker Kamlesh
Published: July 2003

The objective of this study was to assess the pharmacokinetics of diclofenac sodium and its five metabolites following administration of a 150 mg oral dose to healthy subjects and patients with either chronic active hepatitis of varying morphology or alcoholic cirrhosis. Six healthy subjects, 6 chronic active hepatitis patients, and 6 alcoholic cirrhosis patients were enrolled in this prospective, open‐label, parallel study. Blood samples were drawn at 0, 0.25, 0.5, 0.75,1,2,4,6,8,12, 24, 48, 72, 144, 312, and 480 hours, and urine samples were collected for 144 hours after administration of a single oral dose of diclofenac sodium. The mean area under the serum concentration‐time curve extrapolated to infinity, oral clearance, half‐life, maximal concentration, and time to peak concentration for diclofenac and its metabolites were determined and compared using analysis of variance. Cirrhotics had a mean ± SD diclofenac AUC value (19,114 ± 6806ng•h/ml) significantly different (p < 0.02) from hepatitis patients (6071 ± 1867 ng•h/ml) and healthy subjects (7008 ± 2006 ng•hlml), whereas healthy subjects and hepatitis patients had similar values. Comparable results were found for 4′‐hydroxydiclofenac. The AUC values for 3′‐hydroxydiclofenac and 3′‐hydroxy‐4′methoxydiclofeanc were significantly different when healthy subjects were compared to cirrhotics. However, hepatitis subjects were not significantly different from either group. The results indicate that hepatitis does not alter the pharmacokinetics of diclofenac. Alcoholic cirrhosis increased the mean diclofenac AUC approximately three times compared to normal subjects, indicating that one‐third of the usual dose in cirrhotics would produce equivalent AUC values in normal subjects and subjects with alcoholic cirrhosis. However, since pharmacodynamic measurements were not made and no increase in untoward or side effects was noted in the alcoholic cirrhosis patients after a single dose, maintenance doses should be titrated to patient response.
Pharmacokinetic‐Pharmacodynamic Modeling of Testosterone and Luteinizing Hormone Suppression by Cetrorelix in Healthy Volunteers
Authors: Pechstein Birgit , Nagaraja Nelamangala V. , Hermann Robert , Romeis Peter , Locher Mathias , Derendorf Hartmut
Published: July 2003

Cetrorelix (CET), a potent luteinizing hormone‐releasing hormone (LH‐RH) antagonist, was recently approved for the prevention of premature ovulation in patients undergoing a controlled ovarian stimulation (COS), followed by oocyte pickup and assisted reproductive techniques (ART), and is currently under clinical trials for benign prostate hyperplasia, endometriosis, and tumors sensitive to sex hormones. CET suppresses luteinizing hormone (LH), follicle‐stimulating hormone (FSH), and testosterone (T) in men. The purpose of this study was to evaluate the pharmacokinetics and absolute bioavailability of 3 mg intravenously and subcutaneously administered CET in healthy male and female volunteers and to develop a pharmacokinetic‐pharmacodynamic (PK‐PD) model to link the plasma concentrations of CET to the T and LH suppression in males. Following intravenous (IV) (n = 5) and subcutaneous (SC) (n = 6) administration of CET acetate, CET and hormone plasma levels were measured by radioimmunoassay (RIA) and enzyme immunoassay (EIA) methods, respectively. Pharmacokinetics of CET was explained by a three‐compartment model for the TV route and by a two‐compartment model with first‐order absorption for the SC route. Average absolute bioavailability after SC administration was 85%. There were no differences in the pharmacokinetics between male and female subjects (ANOVA, p > 0.05). Single IV and SC doses of CET caused immediate and distinct suppression of LH, FSH, and T levels by 80%, 45%, and 95% of their baseline levels, respectively. The duration of hormone suppression was longer for the SC route. An indirect‐response PK‐PD Emax model was developed to link the measured CET plasma concentrations with the respective T or LH levels. In addition, the circadian rhythm of T levels was accounted by including a cosine function in a second separate PD model The PD model with cosine function was applied to T baseline levels as well as to the suppressed concentrations after CET dosing. The two models adequately described the PK‐PD relationship between plasma levels of CET and T suppression following IV and SC dosing. The EC50 values (mean ± SD) for the suppression of T were similar (p > 0.05) between the two routes of administration and the two models.
Population Pharmacokinetics/Toxicodynamics (PK/TD) Relationship of SAM486A in Phase I Studies in Patients with Advanced Cancers
Authors: Zhou Honghui , Choi Les , Lau Henry , Bruntsch Ute , De Vries Elisabeth E.G.E. , Eckhardt Gail , Van Oosterom A. T. , Verweij Jaap , Schran Horst , Barbet Nicholas , Linnartz Ronald , Capdeville Renaud
Published: July 2003

SAM486A (previously termed CGP 48664), a potent inhibitor of S‐adenosylmethionine decarboxylase, is under clinical development for the treatment of advanced refractory malignancies. Hematological toxicity manifested by dose‐dependent neutropenia has been observed in phase I studies. Population methods were used to investigate pharmacokinetics (PK) as a prognostic factor for safety end point (hematological toxicity) in patients with advanced cancers. SAM486A plasma concentrations and neutrophil counts were collected from three ascending‐dose tolerability and PK studies (study 1: single 5‐day continuous intravenous (IV) infusion with doses ranging from 24–700 mg/m2/cycle; study 2:10‐minute to 3‐hour IV infusion once weekly with doses ranging from 16–325 mg/m2/week; study 3: 1‐hour IV infusion once daily for 5 days with doses ranging from 3.6–202.8 mg/m2/day). The PK of SAM486A were best estimated by a population linear three‐compartment model with NONMEM (version 5) using data from 79 patients in studies 1 through 3. The population pharmacokinetic parameters (SD) were CL = 6.2 (0.4) l/h/m2, Q2 = 15.4(1.5) l/h/m2, Q3, = 33.6 (5.3) l/h/m2, V1 = 9.5 (1.6) l/m2, V2 = 672 (52) l/m2, and V3 = 39.9 (8.3) l/m2, and the corresponding intersubject variability was 45.4%, 74.0%, 85.3%, 80.1%, 37.0%, and 103%, respectively, where CL is total body clearance, Q2 and Q3 are intercompartmental clearances, and V1, V2, and V3 are the volumes of distribution in central and peripheral compartments, respectively. The intrasubject variability was 24.0%. The cumulative AUC before the onset of neutrophil nadir count (AUC) and the duration of exposure over threshold SAM486A concentrations in the range of 0.05 to 0.1 μM based on Bayesian PK parameter estimates significantly correlated with absolute neutrophil count nadir (< 5 × 109/l). AUC showed the best correlation (R2 = 0.72) with absolute neutrophil count nadir by an inhibitory sigmoid Emax model and also correlated with percent decrease in neutrophil count from baseline to nadir by a simple Emax model (R2 = 0.53). Logistic regression analysis indicated that AUC and the duration of exposure over 0.05 to 0.1 μM, but not Cmax, were strong predictors of grade 4 neutropenia (< 0.5 × 109/l). Drug exposure parameters such as AUC derived from population analysis may be used clinically as a useful predictor of drug‐induced neutropenia.
Absorption Characteristics of Sustained‐Release 4‐Aminopyridine (Fampridine SR) in Patients with Chronic Spinal Cord Injury
Authors: MD Jack L. Segal , Hayes Keith C. , Brunnemann Sherry R. , Hsieh Jane T. C. , Potter Patrick J. , Pathak Mayank S. , Tierney David S. , Mason David
Published: July 2003

Fampridine SR (4‐aminopyridine) is a potassium channel‐blocking drug currently being investigated for its therapeutic efficacy in ameliorating central conduction deficits due to demyelination in patients with spinal cord injury (SCI). The present open‐label pharmacokinetic trial examined the absorption characteristics of a sustained‐release form of the drug in 25 SCI subjects with chronic in complete injuries. The overall group mean Cmax of 27.7 ± 6.2 ng/mL occurred at a tmsx of 3.4 ± 1.4 hours. AUC0–12 was 210.5 ± 49.5 ng/mL•h. For paraplegics, AUCtmax was 76.02 ± 33.28 and for tetraplegics was significantly less at 51.25 ± 20.36 (p = 0.037). A statistically significant difference in the initial rate and extent of absorption, but not in total 4‐AP bioavailability over the 12‐hour study period, was evident between tetraplegic patients, 0.60 ± 0.23, and paraplegic patients, 0.39 ± 0.14 (p = 0.02). There was a linear correlation (p < 0.05) between the neurological level of injury and Cmax/AUCtmax. These results confirm and extend previous observations of different rates of drug absorption among SCI patients with lesions above and below the sympathetic outflow (T6) and provide evidence of the absorption characteristics of this sustained‐release form of 4‐aminopyridine, which is helpful for optimal dosing.
Pharmacokinetics and Pharmacodynamics of Peldesine (BCX‐34), a Purine Nucleoside Phosphorylase Inhibitor, following Single and Multiple Oral Doses in Healthy Volunteers
Authors: Viegas Tacey X. , Omura George A. , Stoltz Randall R. , Kisicki James
Published: July 2003

The pharmacokinetic parameters of peldesine (BCX‐34) were investigated after single and multiple oral doses in two groups of healthy adult volunteers. The pharmacodynamic elevation of endogenous inosine and 2′‐deoxyguanosine was simultaneously monitored. The first group of 8 subjects received an intravenous dose (18 mg/m2) and five oral doses (30, 63, 108, 144, and 192 mg/m2) of drug. A second group of 12 subjects received 160 mg/m2 in four and in six divided doses orally Serial blood samples and total urine outputs were collected during dosing and for at least 24 hours after the last dose was administered. One set of samples was analyzed using high‐pressure liquid chromatography/ultraviolet (LC/UV) methods, validated for intact drug in human plasma and urine samples. Another set of samples was analyzed for the biomarkers, inosine and 2′‐deoxyguanosine, using high‐pressure LC with either mass spectrometry (MS) or electrochemical detection (EC) methods. The pharmacokinetic parameters of inosine and 2′‐deoxyguanosine were calculated using noncompartmental methods and correlated against the pharmacokinetic parameters of BCX‐34. For the single‐dose study, the results exhibited linear pharmacokinetics over the dose range from 30 to 144 mg/m2. The calculated terminal half‐life was 3.5 ± 1.0 h, and the absolute bioavailability of the oral formulation was approximately 51%. Analysis of urine in the first 24 hours of collection accounted for approximately 82% of the absorbed intact drug. Evaluation of the multiple‐dose pharmacokinetics indicated that steady‐state blood concentrations were achieved by 24 hours when the drug was administered four or six times a day. A drug dose‐related elevation of plasma 2′‐deoxyguanosine was observed. This phenomenon was not seen with plasma inosine levels. However, analysis of urine samples showed an increase in inosine output with an increase in the drug dose. The calculated terminal half‐life of inosine and 2′‐deoxyguanosine was 15.3 ± 1.8 h and 1.3 ± 0.1 h, respectively.
Flow Cytometric Assessment of Effects of Fluvastatin on Low‐Density Lipoprotein Receptor Activity in Stimulated T‐Lymphocytes from Patients with Heterozygous Familial Hypercholesterolemia
Authors: Raungaard Bent , Brorholt‐Petersen Jens Uffe , Jensen Henrik Kjærulf , Færgeman Ole
Published: July 2003

To test the effects of fluvastatin on low‐density lipoprotein (LDL) receptor activity in patients with heterozygous familial hypercholesterolemia, the authors measured LDL receptor activity in stimulated T‐lymphocytes prepared from 34 patients before and after treatment with 40 mg fluvastatin daily for 12 weeks. Maximally induced pretreatment LDL receptor activities did not correlate with pretreatment plasma cholesterol levels or with changes in plasma cholesterol levels during treatment, and there were no significant changes in LDL receptor activity during treatment. Barring methodological problems, two explanations are possible. Insofar that LDL receptor activity in lymphocytes reflects LDL receptor activity in the liver, the results suggest that the primary response to treatment with fluvastatin in heterozygous familial hypercholesterolemia (FH) patients is not enhanced LDL receptor activity. Alternatively, fluvastatin increases LDL receptor activity in hepatocytes but has little effect on receptor‐dependent lipoprotein catabolism in extrahepatic tissues in vivo.
Prokinetic Effects of Erythromycin after Antimotion Sickness Drugs
Authors: Stewart John J. , Wood Mary J. , Parish Roy C. , Wood Charles D.
Published: July 2003

Motion sickness and the antimotion sickness drugs scopolamine (SCP) and promethazine (PMZ) inhibit gastric emptying (GE). This study was conducted to determine if erythromycin would exert its well‐known prokinetic effects in normal and motion‐sick subjects given antimotion sickness drugs. Fifteen fasted volunteers (11 males, 4 females) participated in the study In control tests, 8 subjects were given intramuscular (IM) saline (SAL, 0.5 ml), SCP (0.1 mg), or PMZ (25 mg). GE of liquid (300 ml) containing 1 mCi of Tc 99m diethylenetria‐minepentaacetic acid (DTPA) was measured by sequential gastric scintigraphy 30 minutes after IM treatments. In other tests, GE was measured in 8 subjects after each IM treatment, followed 10 minutes later by 200 mg of erythromycin thylsuccinate (ESS) suspension given orally. In a third group of tests, 7 subjects received an IM treatment, oral EES 10 minutes later, and were then brought to an advanced level of motion sickness short of vomiting. To induce motion sickness, blindfolded subjects made timed head movements while seated in a rotating chair. GE was measured immediately after rotation. GE half‐life, rate constant, area under the curve (AUC), and lag time were calculated using conventional mathematical methods for analyzing exponential rate processes. GE parameters calculated for normal and motion‐sick subjects given antimotion sickness drugs and EES were compared with those from subjects given IM treatments (control) only. In normal subjects, EES significantly (p < 0.05) increased the GE rate constant for all IM treatments and reduced the AUC for SAL, SCP, and PMZ by 49% (p < 0.05), 44% (p < 0.05), and 69% (p < 0.01), respectively. In motion‐sick subjects, lag time was significantly (p < 0.05) increased, and the rate constant and AUC values were unchanged from control for all IM treatments. The authors conclude that oral EES reverses the gastrostatic actions of the antimotion sickness drugs but does not affect the inhibition of gastric emptying associated with motion sickness. The results suggest that motion sickness and antimotion sickness drugs reduce GE through different mechanisms.
Pharmacokinetics of Ketoprofen Syrup in Small Children
Authors: Kokki Hannu , Liboux Aimé Le , Jekunen Antti , Montay Guy , Heikkinen Marja
Published: July 2003

Ketoprofen is a nonsteroidal anti‐inflammatory drug with analgesic, anti‐inflammatory, and antipyretic properties. Its pharmacokinetics has not been determined in small children. The objective here was to determine the pharmacokinetics of ketoprofen syrup, 0.5 mg/kg, in two groups of 10 children. Group 1 was from ages 6 months up to 2 years (7/10 younger than 1 year), and Group 2 was from ages 2 to 7years. Venous blood samples were collected before drug administration and 0.5, 1, 2, 4, 6, 8, and 12 hours after. A validated HPLC method was used to determine plasma levels of ketoprofen. The lower limit of quantification was 0.02 μg/ml of plasma. Ketoprofen syrup was absorbed rapidly, the plasma level reaching its maximum at 0.5 hours, with C0.5 hours = 3 μg/ml. The pharmacokinetics was similar between the two groups of children. The elimination half‐life, 2.0 hours in Group 1 or 1.9 hours in Group 2, was similar to that reported in adults.
Time to Onset of Analgesia and Analgesic Efficacy of Effervescent Acetaminophen 1000 mg Compared to Tablet Acetaminophen 1000 mg in Postoperative Dental Pain: A Single‐Dose, Double‐Blind, Randomized, Placebo‐Controlled Study
Authors: Møller Philip L. , Nørholt Sven E. , Ganry Hervé E. , Insuasty Jorge H. , Vincent Françoise G. , Skoglund Lasse A. , Sindet‐Pedersen Steen
Published: July 2003

This randomized, double‐blind, placebo‐controlled study compared the time to onset of analgesia and the analgesic efficacy of two formulations of acetaminophen 1000 mg—an effervescent solution and tablet—in 242 patients with moderate or severe pain following dental surgery. Onset of analgesia was determined using a two‐stopwatch procedure. Analgesia was assessed over a 4‐hour period. Treatments were compared using standard indexes of pain intensity and pain relief and summary measures. Both acetaminophen formulations were significantly more effective than their corresponding placebo for all efficacy assessments. The median time to onset of analgesia was significantly shorter with effervescent acetaminophen (20 minutes) compared to tablet acetaminophen (45 minutes). During the first 45 minutes after administration, effervescent acetaminophen was significantly more effective at each scheduled assessment time than tablet acetaminophen. The median time to meaningful pain relief was significantly shorter with effervescent acetaminophen (45 minutes) compared to tablet acetaminophen (60 minutes). At 4 hours after administration, the pain relief was significantly better with tablet acetaminophen than with effervescent acetaminophen. No other significant differences were observed between the active treatments. In conclusion, effervescent acetaminophen produces a significantly faster onset of analgesia than tablet acetaminophen.
Single‐ and Multiple‐Dose Pharmacokinetics of an Oral Once‐a‐Day Osmotic Controlled‐Release OROS® (methylphenidate HC1) Formulation
Authors: Modi Nishit B. , Lindemulder Betsy , Gupta Suneel K.
Published: July 2003

Methylphenidate is used for the treatment of attention deficit hyperactivity disorder (ADHD). OROS® (methylphenidate HCl) is an osmotic controlled‐release delivery system designed for once‐daily oral dosing. The pharmacokinetics of OROS® (methylphenidate HCl) 18 mg qd, sustained‐release (SR) methylphenidate 20 mg qd, and the immediate‐release (IR) formulation given as three 5 mg doses every 4 hours (tid) were compared in adults. In addition, the single‐ and multiple‐dose pharmacokinetics of the OROS® formulation were studied. Following OROS® (methylphenidate HCl), there was a gradual increase in the mean methylphenidate plasma concentrations with peak concentrations noted at 6 to 8 hours. With the SR formulation, peak plasma concentrations were noted at ∼4 hours. Following the IR regimen, methylphenidate plasma concentrations fluctuated in tandem with oral dosing; peak concentrations were noted at 6.5 hours. The terminal half‐life of methylphenidate was similar for the three formulations. The dose‐normalized methylphenidate Cmax for OROS® (methylphenidate HCl) was significantly lower than for IR and SR methylphenidate. The bioavailability of methylphenidate and PPA from OROS® (methylphenidate HCl) relative to the IR and SR formulations was complete. Mean methylphenidate AUC and terminal half‐life were similar after single (32.9 ng•h/mL and 3.9 hours) and multiple doses (35.2 ng•h/mL and 3.9 hours) of OROS® (methylphenidate HCl).
The Pharmacokinetics and Pharmacodynamics of Losartan in Continuous Ambulatory Peritoneal Dialysis
Authors: Pedro Antonio A. , Gehr Todd W. B. , Brophy Donald F. , Sica Domenic A.
Published: July 2003

The pharmacokinetics and pharmacodynamics of losartan and its active metabolite, E‐3174, were studied in 8 stable, hypertensive continuous ambulatory peritoneal dialysis (CAPD) patients. Following a 1‐week washout period, subjects received 100 mg of losartan orally for 7 days. On Days 1 and 7, hemodynamic and hormonal responses were determined, as were PK parameters on Day 7. Peritoneal equilibration testing was performed pre‐ Day 1 and on Day 7. AUC0–24 and t1/2 for losartan and E‐3174 were 95 ± 49.9μg•min/mL and 176 ± 82.1 μg•min/mL and 172.5 ± 86.7 minutes and 628 ± 575 minutes, respectively. These volues are similar to those of normal subjects and subjects on hemodialysis. Peritoneal clearance of losartan and E‐3174 was negligible. All subjects demonstrated a substantial reduction in blood pressure with at least a 10 mmHg drop in diastolic BP. Plasma renin activity (PRA) values increased, but aldosterone, endothelin, norepinephrine, and epinephrine values did not change following 7 days of losartan. Losartan was well tolerated in all study subjects.
Pharmacokinetics and Pharmacodynamics of Sibrafiban, an Orally Administered GP IIb/IIIa Antagonist, following Coadministration of Aspirin and Heparin
Authors: Reimann James D. , Modi Nishit B. , Novotny William
Published: July 2003

Sibrafiban is a double prodrug that is converted to the inactive single prodrug and to the active GP IIb/IIIa antagonist after oral administration. This clinical investigation evaluated whether coadministration of oral aspirin or intravenous heparin would alter the pharmacokinetics or pharmacodynamics of oral sibrafiban. Twenty‐four adult subjects received two of the following four combinations: sibrafiban alone, sibrafiban with ASA, sibrafiban with heparin, and sibrafiban with ASA and heparin, separated by a 2‐week washout period. Concentration profiles of active drug in citrate and EDTA plasma were unchanged with coadministration of ASA or heparin. No pharmacodynamic interaction was seen with coadministration of heparin. Inhibition of platelet aggregation increased 4% to 55%, and Ivy bleeding time increased 58% to 87% with coadministration of sibrafiban and ASA. The combined pharmacodynamic effect of sibrafiban and ASA may indicate a potentially greater therapeutic effect but an increased risk of bleeding when these drugs are used in combination.
Pharmacokinetics and Pharmacodynamics of Tenecteplase: Results from a Phase II Study in Patients with Acute Myocardial Infarction
Authors: Modi Nishit B. , Fox Norma Lynn , Clow Fong‐Wong , Tanswell Paul , Cannon Christopher P , Van de Werf Frans , Braunwald Eugene
Published: July 2003

Tenecteplase is a site‐specific engineered tissue plasminogen activator (t‐PA) variant that can be administered as a single intravenous bolus injection because of its slower plasma clearance. The objective of this study was to investigate the dose‐ranging pharmacokinetics and pharmacodynamics of intravenous bolus tenecteplase compared with intravenous alteplase recombinant t‐PA in patients with acute myocardial infarction. A total of 103 patients received intravenous bolus doses of 30, 40, or 50 mg tenecteplase, and 56 patients received 100 mg rt‐PA as the accelerated 90‐minute infusion regimen in this randomized, open‐label study. Tenecteplase and r‐tPA plasma concentrations were measured for 6 hours. Tenecteplase exhibited biphasic elimination from the plasma with a mean initial half‐life of 22 minutes and a mean terminal half‐life of 115 minutes. The mean plasma clearance was 105 mL/min and did not depend on tenecteplase dose over the dose range studied. In comparison, rt‐PA has a fourfold faster plasma clearance. Pharmacokinetic‐pharmacodynamic evaluation showed that a dose of approximately 0.5 mg/kg results in a plasma AUC value that provides a TIMI 3 flow at 90 minutes that is comparable to that reported with accelerated r‐tPA. In conclusion, tenecteplase has a fourfold slower plasma clearance compared with rt‐PA, allowing dosing as an W bolus injection. Weight‐adjusted dosing of tenecteplase may optimize the therapeutic regimen of tenecteplase.
Coadministration of Tacrolimus and Mycophenolate Mofetil in Stable Kidney Transplant Patients: Pharmacokinetics and Tolerability
Authors: Pirsch John , Bekersky Ihor , Vincenti Flavio , Boswell Garry , Woodle E. Steve , Alak Ala , Kruelle Margaret , Fass Nancy , Facklam David , Mekki Qais
Published: July 2003

The tolerance and pharmacokinetics (PK) of tacrolimus (T) by the addition of mycophenolate mofetil (MMF) in stable kidney transplant patients (6/group) on long‐term tacrolimus‐based therapy were investigated. Patients received combination T and MMF therapy at three MMF doses: 1, 1.5, and 2 g/day administered twice daily. A 12‐hour blood PK profile for T was obtained prior to MMF dosing; concomitant 12‐hour profiles for T, mycophenolic acid (MPA), and mycophenolic acid glucuronide (MPAG) were obtained after 2 weeks of administration. Tolerance was monitored through 3 months. The intra‐ and intergroup PK of T were variable. The mean AUC0–12of T for each group was increased after 2 weeks of concomitant MMF administration, but the increase was not statistically significant. Both drugs were well tolerated. Gastrointestinal events were of interest as such have been attributed to both T and MMF. Events reported were diarrhea, nausea, dyspepsia, and vomiting. Other common adverse events were headache, hypomagnesemia, and tremors. Most were mild, although a few were considered to be moderate. There was no apparent relationship between the incidence of any adverse event and MMF treatment group. In the present study, the coadministration of T and MMF did not significantly alter T pharmacokinetics.
Review: Drug Therapy in Chinese Traditional Medicine
Authors: Cheng Juei‐Tang
Published: July 2003

This article addresses the differences between the basic concepts of drug therapy in Chinese traditional medicine (CTM) and modern Western medicine. In ancient times, throughout the world, humans used plants as food and medicine. In Europe, chemistry developed rapidly after the influence of Paracelsus. Active principles were isolated from plants, and drugs were prepared in the salt form to use as medication. In China, several drugs isolated from plants have been prepared in the salt form in recent years, but herbal medication, developed in the ancient tradition, continued to be widely used in Chinese populations. Some theories such as the yin‐yang theory and the five‐element theory were commonly employed to explain the rationale for the use of CTM. In this review, hypertension and diabetes mellitus are used as examples to illustrate the applications of CTM. The notions of the “whole” and the use of “relative” rather than absolute are important concepts, which distinguish CTM from modern medicine.
Alternative Therapies and Medical Science: Designing Clinical Trials of Alternative/Complementary Medicines—Is Evidence‐Based Traditional Chinese Medicine Attainable?
Authors: Critchley J.A.J.H. , Zhang Ye , Suthisisang Chuthamanee C. , Chan T.Y.K. , Tomlinson B.
Published: July 2003

Evidence‐based traditional Chinese medicine is attainable. With good planning and a positive attitude, the remedies used in traditional Chinese medicine (TCM) and Chinese proprietary medicines can be studied at a standard acceptable to modern science. The identification of an active principal should not delay the search for effective remedies from the TCM pharmacopoeia. Herbal mixtures can be validly tested to establish their efficacy. Problems with potential batch‐to‐batch variation can be circumvented by appropriate randomization. Subsequent independent screening and randomization to treatment and placebo arms can allow for the individualization of treatments by TCM practitioners. However, clearly defined treatments are required and should be recorded in a manner that enables other suitably trained researchers to reproduce them reliably (e.g., using prescriptions in Chinese). Quality control of TCM is a prerequisite of credible clinical trials. Correct natural ingredients must be used without adulteration or erroneous substitution. Evidence of safety in man is essential, and in lieu of data from formal toxicity studies, clear, convincing, and impartial evidence of safety is needed based on their long‐term use in mainstream TCM practice backed up by publications in the Chinese medical/scientific literature.
Rank Power of Metrics Used to Assess QTc Interval Prolongation by Clinical Trial Simulation
Authors: Bonate Peter L.
Published: July 2003

Monte Carlo simulation was used to assess the type I error rate and rank order of power for six different metrics using linear mixed‐effect models, including two variables recommended by the European Agency for the Evaluation of Medicinal Products (EMEA) in the analysis of QTc interval data. The metrics analyzed were maximal change in QTc interval from baseline, maximal QTc interval, area under the QTc interval‐time curve (AUC), average QTc interval, maximal QTc interval with baseline QTc interval as covariate, and AUC with baseline QTc interval as covariate. Two dosing regimens were studied: multiple‐dose oral and multiple‐dose continuous intravenous infusion. Both regimens were designed to produce similar maximal plasma concentrations, albeit with the infusion regimen maintaining maximal plasma concentrations for a longer period of time. The ability of the metrics to detect a drug effect was examined, assuming drug effect followed either an Emax or linear model. All statistics had a type I error rate near the nominal value. Regardless of pharmacokinetic or pharmacodynamic model, AUC with baseline QTc interval as a covariate had greater power than any other metric examined. The simulations also suggest that mean QTc interval data not be used.
Pharmacokinetics, Pharmacodynamics, and Safety of Microencapsulated Octreotide Acetate in Healthy Subjects
Authors: Chen Tianling , Miller Thomas E , Prasad Pratapa , Lee James , Krauss Jayashree , Miscik Kristina , Kalafsky Gaetana , McLeod James E
Published: July 2003

The pharmacokinetics, pharmacodynamics, and safety of the marketed formulation of microencapsulated octreotide acetate were evaluated in an open‐label study in 22 healthy cholecystectomized subjects. Each subject received a single 30 mg dose of microencapsulated octreotide acetate intramuscularly (IM). Concentrations of octreotide, growth hormone (GH), insulin‐like growth factor binding protein 3 (IGFBP‐3), and insulin‐like growth factor 1 (1GF‐1) as well as clinical safety were evaluated over a period of 112 days (16 weeks). After the injection, mean serum octreotide concentration initially increased rapidly, reached the maximum (Cmax, day 1 = 0.96 ± 0.25 ng/ml) approximately 1.5 hours after dosing, and declined thereafter until 24 hours postdose (Cmin, 24 h = 0.088 ± 0.093 ng/ml). The octreotide concentration then increased and started a sustained release from day 7 onward. Plateau concentrations were maintained through day 70 and gradually declined to below the lower limit of quantification (LLOQ) before day 112. The plateau height (Cplateau (2‐112d, 60%)) was 1.68 ± 0.88 ng/ml, and the duration (Δplateau, 60%) was 30.2 ±15.7 days. The integrated concentration‐time curve, AUC0‐112d, was 2819 ± 782 (ng•h/ml), and the apparent half‐life (t1/2) was 169 hours. To assess the variability, the drug concentrations were determined hourly for 8 hours on day 28, and the mean octreotide concentration, Cavg, day 28′ was 1.55 ± 1.26 ng/ml. The suppression of IGF‐1 was statistically significant compared to the baseline (p < 0.05) through day 63; however, there were no appreciable changes in GH and IGFBP‐3 concentrations after a single injection of microencapsulated octreotide acetate. Simulation of a 28‐day dose schedule suggested that steady‐state octreotide concentrations would be reached by the third injection with steady‐state concentrations about twofold greater than the first injection. There were no serious adverse events or clinically meaningful changes in vital signs, ECGs, or laboratory evaluations observed in this study, indicating that the 30 mg IM dose of microencapsulated octreotide acetate was well tolerated in this population.
Pharmacokinetics of Single‐Dose Reboxetine in Volunteers with Renal Insufficiency
Authors: Coulomb François , Ducret Francis , Laneury Jean‐Paul , Fiorentini Francesco , Poggesi Italo , Jannuzzo M. Gabriella , Fleishaker Joseph C. , Houin Georges , Duchêne Patrick
Published: July 2003

Reboxetine is a new selective norepinephrine reuptake inhibitor (selective NRI) for the short‐ and long‐term treatment of depression that is effective and well tolerated at a dose of 8 to 10 mg/day. This study assessed the pharmacokinetics of reboxetine in volunteers with renal impairment. A single 4 mg dose of reboxetine was administered to a total of 18 volunteers with mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment (creatinine clearance: 56–64, 26–51, and 9–19 ml/min, respectively), and reboxetine concentrations were measured in plasma by HPLC. Mean AUC∞ increased by 43% (mild vs. severe; p < 0.01) as renal function declined, while renal clearance and total urinary excretion of unchanged reboxetine decreased by 67% and 62%, respectively (mild vs. severe; p < 0.01 for both parameters). tmax and t1/2 were not significantly different between groups. In comparison with historical data from young healthy volunteers, AUC∞ and t1/2 are at least doubled in volunteers with renal impairment, while CL is halved. This pharmacokinetic study has shown that increasing renal dysfunction leads to increasing systemic exposure to reboxetine, particularly in severe renal insufficiency, although reboxetine was well tolerated by all volunteers. Thus, a reduction of the starting dose of reboxetine to 2 mg twice daily would be prudent in patients with renal dysfunction.
Lack of Effect of a High‐Fat Meal on the Bioavailability of 17β‐Estradiol/Norgestimate in Healthy Postmenopausal Women
Authors: Gisclon L. G. , Curtin C. R. , Larson K. L. , Natarajan J. , Wong F. A. , Morrison D. N. , Bourg D.
Published: July 2003

The effect of a high‐fat meal on the absorption and pharmacokinetics of 17β‐estradiol (E2), estrone (E1), estrone sulfate (E1S), and 17‐deacetylnorgestimate (17d‐NGM) were determined in this two‐way complete crossover study of a single dose of E2/NGM (2 mg/180 μg) in 24 postmenopausal women. Equal numbers of subjects were randomly assigned to two treatment sequences indicated by the order of fed and fasting treatments. Serial blood samples were collected before and after dosing and assayed using validated methods. Food had no effect on the pharmacokinetics of E2, the pharmacologically active estrogen species. Food increased the rates of formation of E1 and E1S and slowed the formation of 17d‐NGM. However, because E1 and E1S are pharmacologically less active metabolites of E2, and since the pharmacokinetic alterations in 17d‐NGM were observed over a short time period, these results are probably of no clinical relevance. The extent of formation of all analytes, as measured by AUC, was not affected by food. In conclusion, administration of a tablet containing 17β‐estradiol/norgestimate (2 mg/180 μg) was safe and well tolerated by healthy postmenopausal women and may be given without regard to the timing of meals in relation to dosing.
A Mass Balance Study to Evaluate the Biotransformation and Excretion of [14C]‐Triamcinolone Acetonide following Oral Administration
Authors: Argenti Domenick , Jensen Bradford K. , Hensel Russell , Bordeaux Kirk , Schleimer Robert , Bickel Carol , Heald Donald
Published: July 2003

The principle objective of this study was to characterize the absorption, metabolism, and disposition of orally administered [14C]‐triamcinolone acetonide. Six healthy male subjects each received a single 100 μCi (≅800 μg) oral dose of [14C]‐triamcinolone acetonide. Plasma, urine, and fecal samples were collected at selected times and analyzed for triamcinolone acetonide and [14C]‐derived radioactivity. Plasma protein binding of triamcinolone acetonide was also determined. Metabolite profiling and identification were carried out in plasma and excreta. Principle metabolites were assessed for activity with in vitro anti‐inflammatory models. [14]‐triamcinolone acetonide was found to be systemically absorbed following oral administration. The presystemic metabolism and clearance of triamcinolone acetonide were extensive, with only a small fraction of the total plasma radioactivity being made up of triamcinolone acetonide. Little to no parent compound was detected in the plasma 24 hours after administration. Most of the urinary and fecally [14C]‐derived radioactivity was also excreted within 24 and 72 hours postdose, respectively. Mean plasma protein binding of triamcinolone acetonide was constant, predictable, and a relatively low 68% over a 24‐fold range of plasma concentrations. Three principle metabolites of triamcinolone acetonide were profiled in plasma, urine, and feces. These metabolites were identified as 6β‐hydroxy triamcinolone, 21‐carboxylic acid triamcinolone acetonide, and 6β‐hydroxy‐21‐oic triamcinolone acetonide. All three metabolites failed to show any concentration‐dependent effects in anti‐inflammatory models evaluating IL‐5‐sustained eosinophil viability and IgE‐induced basophil histamine release.
Current and Emerging Second‐Generation Triptans in Acute Migraine Therapy: A Comparative Review
Authors: Deleu Dirk , Hanssens Yolande
Published: July 2003

Sterile neurogenic inflammation within cephalic tissue, involving vasodilation and plasma protein extravasation, has been proposed as a pathophysiological mechanism in acute migraine. The action of 5‐hydroxytryptamine (5‐HT1B/1D) agonists—so‐called triptans—on receptors located in meningeal arteries (5‐HT1B) and trigeminovascular fiber endings (5‐HT1D) has an inhibitory effect on this neurogenic inflammation. Recently, a series of second‐generation 5‐HT1B/1D agonists (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, and zolmitriptan) have been developed and are reviewed in this article. Their in vitro pharmacological properties, pharmacokinetics, clinical efficacy, drug interactions, and adverse effects are evaluated and compared to the golden standard in the treatment of acute migraine, sumatriptan.
Commentary on the FDA Draft Guidance for Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action: An Industry View
Authors: Harrison Lester I.
Published: July 2003

In June 1999, the Food and Drug Administration issued draft guidance for bioequivalence studies for nasal aerosols and nasal sprays for local action. The purpose of this opinion paper is to highlight the need for a balanced scientific debate before this guidance is used by underscoring the areas in the document that are in opposition to prevailing scientific understanding.
Use of Tangential Visual Symbols to Increase the Long‐Term Learning Process: Applications of Linkage in Teaching Pharmacological Principles of Addiction
Authors: Giannini A. James , Giannini Juliette N. , Condon Maggie
Published: July 2003

Medieval and Renaissance teaching techniques using linkage between course content and tangentially related visual symbols were applied to the teaching of the pharmacological principles of addiction. Forty medical students randomly divided into two blinded groups viewed a lecture. One lecture was supplemented by symbolic slides, and the second was not. Students who viewed symbolic slides had significantly higher scores in a written 15‐question multiple‐choice test 30 days after the lecture. These results were consistent with learning and semiotic models. These models hypothesize a linkage between conceptual content and perception of visual symbols that thereby increases conceptual retention. Recent neurochemical research supports the existence of a linkage between two chemically distinct memory systems. Simultaneous stimulation of both chemical systems by teaching formats similar to those employed in the study can augment neurochemical signaling in the neocortex.