bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of Gender Differences and Large Intrasubject Variability in Cytochrome P450 Activity Measured by Phenotyping with Dextromethorphan
Authors: McCune Jeannine S. , Lindley Celeste , Decker Jodi L. , Williamson Kristin M. , Meadowcroft Amy M. , Graff Donald , Sawyer William T. , Blough David K. , Pieper John A.
Published: July 2003

Gender‐based differences in cytochrome P450 (CYP) activity may occur due to endogenous hormonal fluctuations with the menstrual cycle, which are altered by oral contraceptives. This study assessed the average activity and within‐subject variability in CYP3A4 and CYP2D6 in men, women taking Triphasil®, and regularly menstruating women not receiving oral contraceptives. Thirty‐three healthy volunteers participated in this 28‐day pilot study (12 women receiving Triphasil®) (OCs), 11 regularly menstruating women not on exogenous progesterone or estrogen (no OCs), and 10 men. CYP3A4 and CYP2D6 activities were phenotyped with dextromethorphan (DM) on study days 7,14,21, and 28 using urinary ratios of DM:3‐methoxymorphinan (3MM) and DM:dextrorphan (DX), respectively. Serial blood concentrations of estrogen and progesterone and menstrual diaries were used to determine menstrual phase in both groups of women. Average urinary DM:3MM and DM:DXin the 28 extensive metabolizers of CYP2D6 did not differ between the three study populations (p = 0.86 and 0.93, respectively). Post hoc power analysis indicated that more than 1000 subjects would be needed for 80% power (a = 0.05) to detect a ± 15% difference from the population mean in the urinary ratios of dextromethorphan and its metabolites 3MM and DX. Variability in CYP3A4 and CYP2D6 activity, characterized by intrasubject standard deviation, also did not differ. The varying doses of levonorgesterol and ethinyl estradiol in Triphasil®, fluctuations in estrogen and progesterone, and menstrual phase did not influence CYP3A4 or CYP2D6 activity. It was concluded that CYP3A4 and CYP2D6 activity and intrasubject variability were not different in the three study populations, and thus a clinically important difference between men, women on Triphasil®, and women not receiving oral contraceptives is unlikely. High inter‐ and intrasubject variability in DM:3MM and DM:DX were clearly demonstrated and limit the use of dextromethorphan to phenotype endogenous CYP3A4 and CYP2D6 activity.
Population Pharmacokinetics of Fentanyl in Healthy Volunteers
Authors: Ariano Robert E. , Duke Peter C. , Sitar Daniel S.
Published: July 2003

The authors compared the population pharmacokinetics of fentanyl using a standard individualized modeling (SIM) approach versus that of a nonparametric expectation maximization (NPEM) approach. The pharmacokinetic properties of fentanyl administered as a single 5 ug/kg intravenous infusion were evaluated in 18 healthy volunteers by use of SIM as well as with NPEM. NPEM‐derived parameters were a total body clearance of2.12 0.28 L/kg/h, distributional clearance of 8.43 4.58 L/kg/h, central volume of distribution of 1.22 0.21 L/kg, and peripheral volume of distribution of 1.81 1.47 L/kg. Identified parameter values from the modeling methods resulted in virtually identical simulated profiles; this finding was confirmed when median values noted were not statistically significantly different between modeling methods (SIM or NPEM). However, the NPEM algorithm uniquely identified a greater distributional clearance in the elderly population and also illustrated a profile with at least 10% of the study population having a very high clearance of fentanyl. This finding may affect the therapeutic use of fentanyl. NPEM allows for a more informative global representation of a drug's pharmacokinetics.
A Comparative Multidose Pharmacokinetic Study of Buspirone Extended‐Release Tablets with a Reference Immediate‐Release Product
Authors: Sakr Adel , Andheria Mahalaxmi
Published: July 2003

Buspirone is disclosed in U.S. Patent No. 3,717,634 as a pharmaceutically active compound that has been found to be effective for the treatment of anxiety disorders and depression. In this randomized, two‐treatment, two‐period, multidose crossover study, the pharmacokinetics of a once‐daily extended‐release (ER) formulation of buspirone was compared with that of an immediate‐release (IR) formulation of commercially available buspirone. A total of 30 mg of the ER formulation was administered to 36 healthy volunteers once daily for 7 days, and 15 mg of the IR formulation was administered twice daily for 7 days. Pharmacokinetic profiles of buspirone and its metabolite, 1‐pyrimidinylpiperazine (1‐PP), were obtained at steady state. The bioavailability of buspirone from the ER formulation was more than three times higher than that from the IR formulation at steady state, and that of 1‐PP was about 25% less. The mean steady‐state Cmax of buspirone from the ER formulation was 46% higher than that from the IR formulation (p < 0.05), and that for 1‐PP was lower by 29% (p < 0.05). The mean apparent half‐life of buspirone from the ER formulation (9.04 hours) was considerably longer than that observed for the IR formulation (3.06 hours). The median 1‐PP/buspirone AUC ratio was much higher for the IR formulation at steady state (24.4) than for the ER formulation (6.44). There were no significant differences in average pharmacokinetic metrics observed in men and women. Based on these observations of the potential benefits of once‐daily dosing with the ER product in terms of prolonged buspirone plasma concentrations, a significant in‐crease in the ratio of buspirone to 1‐PP concentration with a lower intersubject variation could be achieved that should provide an improvement in the desired therapeutic effects of buspirone.
Population and Individual Bioequivalence: Lessons from Real Data and Simulation Studies
Authors: Zariffa Nevine M.‐D. , Patterson Scott D.
Published: July 2003

The Food and Drug Administration (FDA) has proposed replacing the 1992 average bioequivalence (ABE) with population and individual bioequivalence (PBE & IBE), as outlined in the preliminary draft guidance of December 1997, which was subsequently replaced by the draft guidances of August 1999 and resolved in the final guidance of October 2000. This has led to considerable public debate among regulatory, academic, and industry experts at numerous conferences (e.g., FDA/AAPS March 1998, FDA/AAPS August‐September 1999, FDA Pharmaceutical Sciences Advisory Committee September 1999) and in the literature. The final guidance calls for ABE to remain as the primary criterion by which new formulations may be judged ready for access to the marketplace. In addition, the FDA recommends the use of replicate study designs for the specific drug classes of controlled release formulations and highly variable drugs. The final guidance also alludes to the possibility of a sponsor requesting alternative criteria such as PBE and IBE following consultation with the FDA. This procedure amounts to a data collection period during which data suitable to evaluate the operating characteristics of PBE and IBE would be generated, analyzed, and discussed among interested parties. A comprehensive review of currently available databases is useful in determining the ultimate value of this data collection period. This report provides an update to the previous publication by the authors. In all, 28 data sets from 20 replicate crossover bioequivalence studies have been analyzed (n = 12–96) using the statistical methodology in the most recent FDA draft guidance. The results are presented below.

Review of the database reveals many interesting features, most notably the lack of consistent results within a given data set across all three criteria. The sensitivity of subject‐by‐formulation interaction to sample size and inherent variability of the compounds is further explored through simulation studies. It is concluded that additional simulation assessments must be considered when evaluating the value of a data collection period for PBE and IBE assessment. It will be shown that definitive conclusions regarding some of the operating characteristics of PBE and IBE can be achieved through a combination of data‐driven hypotheses followed by simulation studies to further evaluate the hypotheses. Some recommendations for further data collection will be made.
Contributions of Five Human Cytochrome P450 Isoforms to the N‐demethylation of Clozapine In Vitro at Low and High Concentrations
Authors: Olesen Ole V. , Linnet Kristian
Published: July 2003

The authors assessed the in vitro contribution of cytochrome P450 (CYP) isoforms 1A2, 3A4, 2C9, 2C19, and 2D6 to the N‐demethylation of clozapine mediated by human liver microsomal preparations (HLM). In contrast to previous studies, the authors focused on a relatively low hepatic concentration level, 5 pM, to assess the conditions at a therapeutically relevant hepatic concentration level of clozapine. The optimal concentrations of specific inhibitors were ini‐tially established using cDNA‐expressed CYP isoforms. The mean contributions of CYPs 1A2, 2C19, 3A4, 2C9, and 2D6 amounted to 30%, 24%, 22%, 12%, and 6%, respectively, with regard to the total HLM‐mediated N‐demethylation.

Thus, the present in vitro study on clozapine N‐demethylation suggests that CYP1A2 is the most important form at low concentrations, which is in agreement with clinical findings. CYP2C19 is also of considerable importance, while the roles of CYP2C9 and 2D6 are more modest. CYP3A4 attained a dominating role with an average contribution of 37% at a high clozapine concentration (50 μM). The rate of other metabolic routes mediated by CYP2D6 only corresponded to about one fifth of the CYP2D6catalyzed N‐demethylation rate.
The Safety of Higher Than Standard Dose of Doxylamine‐Pyridoxine (Diclectin®) for Nausea and Vomiting of Pregnancy
Authors: Atanackovic Gordana , Navioz Yvette , Moretti Myla , Koren Gideon
Published: July 2003

A delayed‐release combination of doxylamine‐pyridoxine (D‐P) (Diclectin®) is the only approved antiemetic medication for use in pregnancy in Canada. The standard recommended dose is up to 4 tablets a day, regardless of body weight or severity of symptoms. The objective of this study was to determine the incidence of adverse maternal and fetal effects and pregnancy outcome in 225 women taking Diclectin® at the recommended (n = 123) or higher than recommended (n = 102) doses. In this observational, prospective study, one‐third (33.6%) of women reported having adverse effects (sleepiness, tiredness, and/or drowsiness) temporally related to the medication. There was no association between the dose per kg and rates of reported maternal adverse effects with doses ranging from 0.1 mg/kg to 2.0 mg/kg (1–12 tablets). Nausea and vomiting of pregnancy (NVP) was reported as severe by the majority (75.8%) of women. Mean birth weight (BW) was 3400 g and gestational age (GA) 39 weeks. Multivariate analysis revealed that only prepregnancy weight and GA predicted lower BW, not the dose of D‐P or the severity of NVP. There were two pregnancies with major malformation, a finding that is consistent with the rates of birth defects in the general population. It was concluded that the higher than standard dose of Diclectin®, when calculated per kg of body weight, does not affect either the incidence of maternal adverse effects or pregnancy outcome. If needed, Diclectin® can be given at doses higher than 4 tablets/day to normalize for body weight or optimize efficacy.
Measurement of Acetaminophen‐Protein Adducts in Children and Adolescents with Acetaminophen Overdoses
Authors: James Laura P , Farrar Henry C. , Sullivan Janice E. , Givens Timothy G. , Kearns Gregory L. , Wasserman Gary S. , Walson Philip D. , Hinson Jack A. , Pumford Neil R.
Published: July 2003

Acetaminophen‐protein adducts are biomarkers of acetaminophen toxicity present in the centrilobular region of the liver of laboratory animals following the administration of toxic doses of acetaminophen. These biomarkers are highly specific for acetaminophen‐induced hepatic injury and correlate with hepatic transaminase elevation. The objective of this prospective, multicenter study was to evaluate the clinical application of the measurement of acetaminophen‐protein adducts in pediatric acetaminophen overdose patients. Serum samples were obtained from 51 children and adolescents with acetaminophen overdose at the time ofrou‐ tine blood sampling for clinical monitoring. Six subjects developed “severe” hepatotoxicity (transaminase elevation > 1000IU/L), and 6 subjects had transaminase elevation of 100 to 1000 IU/L. Acetaminophen‐protein adducts were detected in the serum of only 1 study subject, a patient with marked transaminase elevation (> 6000 IU/L) and high riskforthe development of hepatotoxicity according to the Rumack nomogram. While this study provides further support for the occurrence of covalent binding of acetaminophen to hepatic protein in humans following acetaminophen overdose, the detection of acetaminophen‐protein adducts in serum with the current methodology requires significant biochemical evidence of hepatocellular injury.
Comparison of Azathioprine and Mycophenolate Mofetil for the Prevention of Acute Rejection in Recipients of Pancreas Transplantation
Authors: Oh Jung M. , Wiland Anne M. , Klassen David K. , Weidle Paul J. , Bartlett Stephen T.
Published: July 2003

The study was performed to compare the efficacy and side effects of azathioprine (AZA) and mycophenolate mofetil (MMF) in conjunction with cyclosporine or tacrolimus and steroids for the prevention of acute pancreas rejection during the first 6 months of pancreas transplantation. In this case‐controlled study, MMF is compared with historical controls of AZA in the prevention of acute pancreas rejection. The primary measures of treatment efficacy were patient and pancreas survival rate at 6 months after transplantation. Secondary efficacy measures were the occurrence of biopsyproven pancreas rejections and the use of antilymphocyte preparations for rejection treatment. A total of 111 pancreas transplant patients (57 in the AZA group and 54 in the MMF group) were evaluated. The 6‐month patient survival rate was 96% in the AZA group versus 97% in the MMF group(p = 0.57).The 6‐month pancreas graft survival rate was 88% in the AZA group versus 91% in the MMF group(p = 0.29).However, biopsy‐proven rejection episodes during the first 6 months of transplantation were significantly lower with MMF (46%) than with AZA (69%)(p = 0.01).In addition, patients in the AZA group received a greater number of full courses of antilymphocyte therapy as a rejection treatment(p = 0.004).Overall, the frequency of adverse events was similar, although the MMF group experienced higher incidences of gastrointestinal adverse events. In conclusion, compared with AZA, MMF significantly reduces the rate of biopsy‐proven pancreas rejection during the first 6 months of transplantation and is well tolerated, except for gastrointestinal adverse events.
Intravenous Safety and Pharmacokinetics of a Novel Dimerizer Drug, AP1903, in Healthy Volunteers
Authors: Iuliucci John D. , Oliver Stuart D. , Morley Steve , Ward Chris , Ward Janet , Dalgarno David , Clackson Tim , Berger Harvey J.
Published: July 2003

AP1903 is a novel gene‐targeted drug that is being developed for use in drug‐regulated cell therapies. An intravenous, single‐blind, placebo‐ and saline‐controlled, ascending‐dose study was performed to evaluate the safety, tolerability and pharmacokinetics of AP1903. Twenty‐eight normal healthy male volunteers were randomized into five dosage groups of AP1903 (0.01, 0.05, 0.1, 0.5, and 1 mg/kg). Within each group, 4 volunteers received a single dose of AP1903, 1 volunteer received an equal volume of placebo, and 1 received an equal volume of normal saline. The only exception was in the 0.5 mg/kg group, in which 4 volunteers were dosed: 3 received AP1903 and 1 received normal saline. All dosages were administered as intravenous infusions over 2 hours. Clinical safety parameters were monitored, and serial blood and urine samples were collected for analysis of AP1903. No drug‐related adverse events were observed at any of the dose levels with the possible exception of facial flushing in 1 volunteer at the 1.0 mg/kg dose level. AP1903 plasma levels were directly proportional to the administered dose, with mean Cmax values ranging from approximately 10 to 1275 ng/mL over the 0.01 to 1.0 mg/kg dose range. Following the infusion period, blood concentrations revealed a rapid distribution phase, with plasma levels being reduced to approximately 18%, 7%, and 1% of the maximal concentration at 0.5, 2, and 10 hours postdose, respectively. AP1903 was shown to be safe and well tolerated at all dose levels and demonstrated a favorable pharmacokinetic profile at doses well above the anticipated therapeutic dose.
Pharmacokinetics and Safety of FFR‐rFVIIa after Single Doses in Healthy Subjects
Authors: Erhardtsen Elisabeth , Nilsson Povl , Johannessen Marie , Thomsen Mikael S.
Published: July 2003

FFR‐rFVIIa is an antithrombotic agent, which has also proven to have antirestenotic properties in animal models. FFR‐rFVIIa is a modified recombinant FVIIa in which the catalytic site is irreversibly inactivated by a synthetic tripeptide covalently bound with the FVIIa molecule. The modified rFVIIa retains its tissue factor (TF) binding capacity but is otherwise enzymatically inactive. A double‐blind, placebo‐controlled, randomized dose escalation trial was conducted to investigate eight single i.v. doses of FFR‐rFVIIa (0.01, 0.02, 0.05, 0.08, 0.12, 0.18, 0.27, or 0.40 mg/kg body weight) in healthy male volunteers (n = 62). Safety, pharmacokinetics, and pharmacodynamics of FFR‐rFVIIa were assessed. Mean (SD) AUC0‐∞ ranged from 0.35 (0.11)to 28.8 (3.5) g•h/ml, and mean Cmax ranged from 0.078 (0.019) to 4.8 (0.7) g/ml. The mean elimination half‐life ranged from 3.8 to 5.8 hours. Mean AUC0‐∞ increased with increasing dose levels. Cmax appeared to be proportional to the dose level, with the exception of the lowest dose level. A dose‐dependent prolongation of the prothrombin time was found, demonstrating that FFR‐rFVIIa inhibited coagulation via the TF‐dependent pathway. FFR‐rFVIIa was generally well tolerated at all dose levels studied.
A Pharmacokinetic Study of Intramuscular (IM) Parecoxib Sodium in Normal Subjects
Authors: Karim Aziz , Laurent Aziz , Slater Margaret E. , Kuss Michael E. , Qian Jiang , Crosby‐Sessoms Sharon L. , Hubbard Richard C.
Published: July 2003

A single‐center, double‐blind, placebo‐controlled, randomized study was conducted to determine the pharmacokinetics, safety, and tolerability of single, rising intramuscular (IM) doses and the single maximum tolerated dose of parecoxib sodium, a prodrug of the novel COX‐2 selective anti‐inflammatory analgesic drug valdecoxib, in 56 healthy male volunteers, ages 18 to 45 years inclusive. Cohorts of up to 6 subjects in each dose schedule were administered either parecoxib sodium (1 mg, 2 mg, 5 mg, 10 mg, 20 mg, or 40 mg) or matching placebo. Following IM administration, serial blood samples for measurement of plasma concentrations of parecoxib, valdecoxib, and valdecoxib metabolite (M1) were collected at predetermined intervals (from 15 minutes prior to dose and through 96 hours postdose). Urine collections were obtained for drug assay (from −12 to 0 hours, 0 to 12 hours, and 12 to 24 hours postdose). After IM administration, peak plasma concentrations of parecoxib were reached within 15 minutes and then declined rapidly as prodrug was converted to the active moiety, valdecoxib. Change in plasma concentrations of valdecoxib, which declined more slowly (t1/2 = 5.4–9.9 hours), reflected transformation to several metabolites, one of which was the minor active metabolite M1. As measured by the AUC0–∞, Cmax, and XU0–24 of valdecoxib, parecoxib sodium demonstrated dose proportionality when administered in the range of 1 mg to 40 mg of parecoxib. All single IM doses up to the maximum of 40 mg of parecoxib, as well as concentrations of up to 20 mg/ml, were well tolerated.
Lack of Pharmacokinetic Interaction between Rofecoxib and Methotrexate in Rheumatoid Arthritis Patients
Authors: Schwartz Jules I. , Agrawal Nancy G. B. , Wong Peggy H. , Bachmann Kenneth A. , Porras Arturo G. , Miller Jutta L. , Ebel David L. , Sack Marshall R. , Holmes Gregory B. , Redfern Jan S. , Gertz Barry J.
Published: July 2003

Rofecoxib is a highly selective and potent inhibitor of cyclooxgenase‐2 (COX‐2). Methotrexate is a disease‐modifying agent with a narrow therapeutic index frequently prescribed for the management of rheumatoid arthritis. The objective of this study was to investigate the influence of clinical doses of rofecoxib on the pharmacokinetics of methotrexate in patients with rheumatoid arthritis. This was a randomized, double‐blind, placebo‐controlled study in 25 rheumatoid arthritis patients on stable doses of methotrexate. Patients received oral methotrexate (7.5 to 20 mg) on days‐1, 7,14, and 21. Nineteen patients received rofecoxib 12.5, 25, and 50 mg once daily on days 1 to 7, 8 to 14, and 15 to 21, respectively. Six patients received placebo on days1 to 21 only to maintain a double‐blinded design for assessment of adverse experiences. Plasma and urine samples were analyzed for methotrexate and its major although inactive metabolite, 7‐hydroxymethotrexate. The AUC00–∞ geometric mean ratios (GMR) and their 90% confidence intervals (90% CI) (rofecoxib + methotrexate/methotrexate alone) for day 7/day −1, day 14/day‐1, and day 21/day −1, for rofecoxib 12.5, 25, and 50 mg, were 1.03 (0.93, 1.14), 1.02 (0.92, 1.12), and 1.06 (0.96, 1.17), respectively (p > 0.2 for all comparisons to day −1). All AUC0–∞ GMR and Cmax GMR 90% CIs fell within the predefined comparability limits of (0.80, 1.25). Similar results were observed for renal clearance of methotrexate and 7‐hydroxymethotrexate at the highest dose of rofecoxib tested (50 mg). It was concluded that rofecoxib at doses of 12.5, 25, and 50 mg once daily has no effect on the plasma concentrations or renal clearance (tested at the highest dose of rofecoxib) of methotrexate in rheumatoid arthritis patients.
The Effects of Tegaserod (HTF 919) on the Pharmacokinetics and Pharmacodynamics of Digoxin in Healthy Subjects
Authors: Zhou Honghui , Ledford Patricia C. , Hubert Martine , Appel‐Dingemanse Silke , Osborne Stuart , McLeod James F.
Published: July 2003

Tegaserod (HTF 919) is a highly specific 5‐HT4 receptor partial agonist that exhibits promotile activity throughout the gastrointestinal tract and is under development for the treatment of functional gastrointestinal motility disorders. The present study was designed to assess the effect of multiple doses of tegaserod on the single‐dose pharmacokinetics and pharmacodynamics of digoxin, a commonly prescribed agent for congestive heart failure. The study was an open‐label, randomized, two‐period crossover design of 12 healthy subjects. One treatment included digoxin treatment alone; the other treatment included a combined digoxin and tegaserod treatment. On day 1 of the digoxin treatment period, subjects received a single 1 mg oral dose of digoxin. In the combined tegaserod/digoxin treatment period, subjects received a single oral dose of 1 mg digoxin after 3 days of tegaserod (6 mg bid). After coadministration of tegaserod, systemic exposure to digoxin was decreased; mean AUC decreased by 11.9% (p < 0.05) relative to digoxin alone. Cmax was decreased by about 15% (p < 0.05). The 0.5‐hour difference in the median tmax between the two treatments was not statistically significant. Because the steady‐state trough concentration of digoxin (Css,min) correlates with pharmacological effects, Css,minfor digoxin alone and in combination with tegaserod was simulated based on both parametric compartmental modeling and nonparametric superpositioning approaches. The predicted arithmetic mean Css,minfor combination therapy is 86% to 89% of that following digoxin alone. Likewise, the predicted arithmetic mean steady‐state peak concentration (Css,max) and AUC at steady state during a dosing interval (AUCss,τ) have a similar decrease. This extent of decrease in systemic exposure of digoxin at steady state is unlikely to be clinically relevant. Administration of tegaserod (6 mg bid) was well tolerated, both alone and in combination with a single dose of digoxin. There were no pharmacodynamic changes in ventricular rate and QT interval following coadministration of tegaserod with digoxin. The 1.5‐hour and 2‐hour postdose plasma concentrations of tegaserod on days 3 and 4 confirmed adequate exposure. In conclusion, dose adjustment for digoxin is unlikely to be needed when tegaserod is coadministered.
Relative Contribution of CYP3A to Amitriptyline Clearance in Humans: In Vitro and In Vivo Studies
Authors: Venkatakrishnan Karthik , Schmider Jürgen , Harmatz Jerold S. , Ehrenberg Bruce L. , von Moltke Lisa L. , Graf Jennifer A. , Mertzanis Polyxane , Corbett Kathleen E. , Rodriguez Molly C. , Shader Richard I. , Greenblatt David J.
Published: July 2003

The relative contribution of cytochrome P450 3A (CYP3A) to the oral clearance of amitriptyline in humans has been assessed using a combination of in vitro approaches together with a clinical pharmacokinetic interaction study using the CYP3A‐selective inhibitor ketoconazole. Lymphoblast‐expressed CYPs were used to study amitriptyline N‐demethylation and E‐10 hydroxylation in vitro. The relative activity factor (RAF) approach was used to predict the relative contribution of each CYP isoform to the net hepatic intrinsic clearance (sum of N‐demethylation and E‐10 hydroxylation). Assuming no extrahepatic metabolism, the model‐predicted contribution of CYP3A to net intrinsic clearance should equal the fractional decrement in apparent oral clearance of amitriptyline upon complete inhibition of the enzyme. This hypothesis was tested in a clinical study of amitriptyline (50 mg, PO) with ketoconazole (three 200 mg doses spaced 12 hours apart) in 8 healthy volunteers. The RAF approach predicted CYP2C19 to be the dominant contributor (34%), with a mean 21% contribution of CYP3A (range: 8%‐42% in a panel of 12 human livers). The mean apparent oral clearance of amitriptyline in 8 human volunteers was decreased from 2791 ml/min in the control condition to 2069 ml/min with ketoconazole. The average 21% decrement (range: 2%‐40%) was identical to the mean value predicted in vitro using the RAF approach. The central nervous system (CNS) sedative effects of amitriptyline were slightly greater when ketoconazole was coadministered, but the differences were not statistically significant. In conclusion, CYP3A plays a relatively minor role in amitriptyline clearance in vivo, which is consistent with in vitro predictions using the RAF approach.
Effects of Low‐Dose Pravastatin on Plasma Levels of Lipids and Apolipoproteins in Japanese Type II Hyperlipoproteinemic Subjects with Apolipoprotein E Phenotype E3/2, E3/3, and E4/3
Authors: Kobayashi Toshio , Homma Yasuhiko
Published: July 2003

Effects of 12 weeks of treatment with pravastatin at a dose of 20 mg/day were compared in subjects with type II hyperlipoproteinemia with apo+(lipoprotein) E phenotype E3/2, E3/3, and E4/3. There were no differences in age, body mass index, smoking status, complications, or plasma levels of lipids and apoproteins, except the higher levels of apo E in E3/2 subjects (n = 11) than in E3/3 subjects (n = 84) and E4/3 subjects (n = 28). Plasma levels of low‐density lipoprotein cholesterol (LDL‐C) were reduced by 47% ± 8% (mean ± SD) in E3/2 subjects, 36% ± 10% in E3/3 subjects, and 26% ± 12% in E4/3 subjects after 12 weeks of treatment with pravastatin (all p < 0.0001). Plasma levels of apo B were decreased by 40% ± 12% in E3/2 subjects, 27% ± 10% in E3/3 subjects, and 18% ± 14% in E4/3 subjects after 12 weeks of treatment with pravastatin (all p < 0.0001). The reduction in plasma levels of LDL‐C and apo B was most marked in E3/2 subjects, next in E3/3 subjects, and smallest in E4/3 subjects. The authors conclude that treatment with pravastatin at a dose of 20 mg/day in Japanese subjects is equally effective as 40 mg/day in Western subjects, and apo E polymorphism is a factor to determine the efficacy of pravastatin in Japanese subjects.
Seville (sour) Orange Juice: Synephrine Content and Cardiovascular Effects in Normotensive Adults
Authors: Penzak Scott R. , Jann Michael W , Cold Julie A. , Hon Yuen Yi. , Desai Hiral D. , Gurley Bill J.
Published: July 2003

The Seville orange extract Citrus aurantium contains m‐synephrine (phenylephrine) and octopamine; it causes cardiac disturbances in animals and is used by humans for weight loss. Juice from the orange (Seville orange juice [SOJ]) is used to “knock out” intestinal cytochrome P450 (CYP) 3A4 in bioavailability studies. The purpose of this study was to determine synephrine and octopamine concentrations in SOJ and SOJ's cardiovascular effects in normotensive humans. Subjects consumed 8 ounces of SOJ and water in crossover fashion followed by a repeat ingestion 8 hours later. Hemodynamic (heart rate; systolic, diastolic, and mean arterial pressure) measurements followed. Synephrine and octopamine were determined by high‐performance liquid chromatography. Hemodynamics did not differ significantly between water and SOJ groups. Mean synephrine concentration of SOJ samples was 56.9 ± 0.52 μg/ml; octopamine was not detected. SOJ ingestion by normotensive subjects is expected to be safe. Individuals with severe hypertension, tachyarrhythmias, and narrow‐angle glaucoma and monoamine oxidase inhibitor recipients should avoid SOJ consumption. Persons taking decongestant‐containing cold preparations should also refrain from SOJ intake.
The Pharmacokinetics of Enalapril in Children and Infants with Hypertension
Authors: Wells Thomas , Rippley Ronda , Hogg Ronald , Sakarcan Abdullah , Blowey Douglas , Walson Philip , Vogt Beth , Delucchi Angela , Lo Man‐Wai , Hand Elizabeth , Panebianco Deborah , Shaw Wayne , Shahinfar Shahnaz
Published: July 2003

Forty children with hypertension between the age of 2 months and 15 years received 0.07 to 0.14 mg/kg of enalapril as a single daily dose. Enalapril was administered orally as a novel extemporaneous suspension in children younger than 6 years of age and as tablets in older children. First‐dose and steady‐state pharmacokinetics were estimated in children ages 1 to 24 months, 25 months to < 6 years, 6 to < 12 years, and 12 to < 16 years. Maximum serum concentrations for enalapril occurred approximately 1 hour after administration. Serum concentrations of enalaprilat, the active metabolite of enalapril, peaked between 4 and 6 hours after the first dose and 3 and 4 hours after multiple doses. The area under the concentration versus time curve (AUC), adjusted for body surface area, did not differ between age groups. Based on comparison of first‐dose and steady‐state AUCs, the accumulation of enalaprilat in children ranged from 1.13‐ to 1.45‐ fold. For children ages 2 to 15 years, mean urinary recovery of total enalaprilat ranged from 58.3% in children ages 6 to < 12 years to 71.4% in children ages 12 to < 16 years. Urinary recovery for children ages 2 to < 6 years was 66.8%. The mean percentage conversion of enalapril to enalaprilat ranged from 64.7% for children ages 1 to 24 months to 74.6% for children ages 6 to < 12 years. The median effective half‐life for accumulation ranged from 14.6 hours in children ages 12 to < 16 years to 16.3 hours in children ages 6 to < 12 years. There were two serious adverse events, neither of which was attributed to enalapril or resulted in discontinuation of the study drug. The extemporaneous suspension used in this study was tolerated well. The pharmacokinetics of enalapril and enalaprilat in hypertensive children ages 2 months to 15 years with normal renal function appears to be similar to that previously observed in healthy adults.
Pharmacokinetics and Tolerability of GW420867X, a Nonnucleoside Reverse Transcriptase Inhibitor, following Single Escalating Doses in Healthy Male Volunteers
Authors: Moore Katy H. P. , Cass Lindsey M. , Dallow Nigel , Hardman Timothy C. , Jones Anne , Boyce Malcolm , Prince William T.
Published: July 2003

The aim of the current study was to characterize the pharmacokinetics of GW420867X, a new nonnucleoside reverse transcriptase inhibitor, using a single escalating dose protocol in healthy volunteers. Four dose levels were investigated in sequential order: 300, 600, 900, and 1200 mg, with a ratio of 4:1 subjects receiving active or placebo treatment, respectively. Following single‐dose administration, GW420867X was readily absorbed with a median time to peak concentration of 3 to 5 hours. GW420867X plasma exposure (AUC) was dose proportional but variable within the 300 to 1200 mg dose range. Less than dose‐proportional increases were observed for Cmax. The terminal elimination t1/2 was 50 hours, which supports once‐daily dosing in future studies. Plasma trough concentrations of GW420867X at 24 hours after dosing were many fold greater than the in vitro IC50 HIV‐1HXB2 in MT4 cells. GW420867X was generally well tolerated following single‐dose administration up to 900 mg; increased central nervous system‐related adverse events were observed at higher doses. GW420867X had a favorable pharmacokinetic and safety profile that would enable this drug to be explored in future clinical studies with HIV‐1 infected patients at doses that would provide appropriate safety and efficacy.
Dose Proportionality of Oral Etoricoxib, a Highly Selective Cyclooxygenase‐2 Inhibitor, in Healthy Volunteers
Authors: Agrawal Nancy G. B. , Porras Arturo G. , Matthews Catherine Z. , Woolf Eric J. , Miller Jutta L. , Mukhopadhyay Saurabh , Neu Donald C. , Gottesdiener Keith M.
Published: July 2003

To assess dose proportionality of etoricoxib across the anticipated clinical dose range, a single panel of 12 healthy subjects was administered single oral doses of etoricoxib of 5,10, 20, 40, and 120 mg in an open, two‐part, five‐period crossover study. Plasma samples were collected after each dose and analyzed for etoricoxib concentrations. The pharmacokinetics of etoricoxib appear to be linear over the entire dose range examined, from 5 to 120 mg. Etoricoxib was found to be well tolerated across the 5 to 120 mg dose range.
Human Drug Metabolism and the Cytochromes P450: Application and Relevance of In Vitro Models
Authors: Venkatakrishnan Karthik , von Moltke Lisa L. , Greenblatt David J.
Published: July 2003

The cytochromes P450 (CYPs) constitute a superfamily of hemoprotein enzymes that are responsible for the biotransformation of numerous xenobiotics, including therapeutic agents. Studies of the biochemical and enzymatic properties of these enzymes and their molecular genetics and regulation of gene expression and activity have greatly enhanced our understanding of several aspects of clinical pharmacology such as pharmacokinetic variability, drug toxicity, and drug interactions. This review evaluates the major human hepatic drug‐metabolizing CYP enzymes and their clinically relevant substrates, inhibitors, and inducers. Also discussed are the molecular bases and clinical implications of genetic polymorphisms that affect the CYPs. Much of the information on the specificity of substrates and inhibitors of the CYP enzymes is derived from in vitro studies using human liver microsomes and heterologously expressed CYP enzymes. These methods are discussed, and guidelines are provided for designing enzyme kinetic and reaction phenotyping studies using multiple approaches. The strengths, weaknesses, and discrepancies among the different approaches are considered using representative examples. The mathematical models used in predicting the pharmacokinetic clearance of a drug from in vitro estimates of intrinsic clearance and the principles of quantitative in vitro‐in vivo scaling of metabolic drug interactions are also discussed.
Prednisolone Pharmacokinetics and Pharmacodynamics in Relation to Sex and Race
Authors: Magee Mindy He , Blum Robert A. , Lates Christian D. , Jusko William J.
Published: July 2003

Prednisolone pharmacokinetics (PK) and pharmacyodynamics (PD) were investigated in relation to sex and race in white males, black males, white females, and black females (n = 8/group) after a single oral dose (0.27 mg/kg) of prednisone. The study consisted of baseline and prednisone phases with 32‐hour sampling in each phase. Women were studied during the luteal phase of their menstrual cycle. Total and free plasma prednisolone concentrations were assayed by HPLC and ultrafiltration, and pharmacokinetic data were analyzed by compartmental fitting using WinNonlin. Plasma cortisol concentrations were assayed by HPLC; T‐helper, T‐suppressor lymphocyte, and neutrophil cell counts were determined by FACS and hemocytometry, and these pharmacodynamic data were evaluated by basic and extended indirect response models using ADAPT II. Total body weight‐normalized free prednisolone oral clearance and apparent volume of distribution were higher in men compared with women, regardless of race (by 22% in whites and 40% in blacks for oral clearance, p < 0.01; by 32% in whites and 38% in blacks for apparent volume of distribution, p < 0.01). The 50% inhibitory concentration (IC50) values for T‐suppressor cell‐trafficking inhibition were higher in whites than in blacks, regardless of sex (by 125% in men and 208% in women, p < 0.01). The IC50 or SC50 values for effects of prednisolone on cortisol secretion and T‐helper lymphocyte or neutrophil trafficking were not statistically different between men and women, blacks and whites. The findings of this study suggest that there are some prednisolone PK/PD differences related to sex and race. However, these differences do not suggest the need for dosage adjustments, and additional experiments with repeat dosing are needed to fully evaluate the clinical implication of these findings.
Pharmacokinetics of Gemtuzumab Ozogamicin, an Antibody‐Targeted Chemotherapy Agent for the Treatment of Patients with Acute Myeloid Leukemia in First Relapse
Authors: Dowell James A. , Korth‐Bradley Joan , Liu Hanjiu , King S. Peter , Berger Mark S.
Published: July 2003

The purpose of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin (Mylotarg™; Wyeth‐Ayerst Laboratories, St. Davids, PA) in patients with acute myeloid leukemia (AML) in first relapse. Gemtuzumab ozogamicin is an antibody‐chemotherapeutic conjugate characterized as antibody‐targeted chemotherapy, consisting of an engineered human anti‐CD33 antibody (hP67.6) linked to a potent cytotoxic agent, N‐acetyl‐gamma calicheamicin DMH. The pharmacokinetics of gemtuzumab ozogamicin was evaluated in 59 adult AML patients in first relapse, enrolled in a phase II study. Plasma was collected following each dose at specified times, and the pharmacokinetics was characterized by measures of hP67.6, total calicheamicin derivatives, and unconjugated calicheamicin derivatives. After administration of the first 9 mg/m2 dose of gemtuzumab ozogamicin, the pharmacokinetic parameters (mean ± SD) of hP67.6 following the first dose were as follows: peak plasma concentration, 2.86 ± 1.35 mg/L;AUC, 123 ± 105 mg·h/L;t1/2, 72.4 ± 42.0 hours; and clearance, 0.265 ± 0.229 L/h. Increased concentrations were observed after the second dose and are believed to be due to a decrease in clearance by CD33‐positive blast cells, a result of the reduced tumor burden following the first dose. The concentration profiles of calicheamicin followed the same time course as hP67.6, evidence that calicheamicin remained conjugated to the antibody and delivered to leukemic cells. No relationship was found between plasma concentration and response at the recommended dose. The pharmacokinetics of gemtuzumab ozogamicin has been characterized in AML patients receiving doses at the proposed therapeutic level.
Comparative Pharmacokinetics and Pharmacodynamics of Amlodipine in Hypertensive Patients with and without Type II Diabetes Mellitus
Authors: Preston Richard A. , Chung Menger , Gaffney Michael , Alonso Alberto , Baltodano Neyton M. , Epstein Murray
Published: July 2003

Recent clinical trials aimed at attenuating complications in diabetes mellitus have generated interest in the impact of drug formulation and altered pharmacokinetics and pharmacodynamics in diabetes. Specifically, it has been proposed that the diabetic state may alter the pharmacokinetics of several cardiovascular drugs, including some calcium antagonists. The present study investigates the effects of diabetes mellitus on the pharmacokinetics and pharmacodynamics of amlodipine in hypertensive subjects with and without diabetes mellitus to determine whether the diabetic state alters these parameters. This trial consisted of a 2‐week placebo washout phase, a 2‐week titration phase, and a 2‐week maintenance phase. Study patients included 18 hypertensive patients with type II diabetes mellitus and 10 nondiabetic hypertensive patients. Blood samples were collected after administration of amlodipine and AUC, Cmax, and tmax were determined. The acute 24‐hour pharmacodynamic response to amlodipine was assessed by blood pressure and telemetric heart rate measurements. There were no significant differences for either amlodipine 5 or 10 mg in AUC (p = 0.40 for 5 mg; p = 0.59 for 10 mg), Cmax (p = 0.41 for 5 mg; p = 0.45 for 10 mg), and tmax (p = 0.79 for 5 mg; p = 0.67 for 10 mg) between diabetic and nondiabetic hypertensive subjects. Similarly, the 24‐hour pharmacodynamic effects of amlodipine on systolic blood pressure, diastolic blood pressure, and heart rate did not differ between diabetic and nondiabetic subjects as assessed by repeated‐measures analysis of variance. Because of the theoretical basis for anticipating that diabetes mellitus may provoke important pharmacokinetic and pharmacodynamic alterations, our study provides an important database in clearly demonstrating that the diabetic milieu did not alter the pharmacokinetics or pharmacodynamics of amlodipine.
Onset of Analgesia for Liquigel Ibuprofen 400 mg, Acetaminophen 1000 mg, Ketoprofen 25 mg, and Placebo in the Treatment of Postoperative Dental Pain
Authors: Olson Ms. Nancy Z. , Otero Angel M. , Marrero Ivan , Tirado Ms. Sylma , Cooper Stephen , Doyle Geraldine , Jayawardena Shyamalie , Sunshine Abraham
Published: July 2003

Ibuprofen is a peripherally acting nonsteroidal anti‐inflammatory drug indicated for analgesia, antipyresis, and various arthritic conditions. A solubilized 200 mg liquigel formulation of ibuprofen has been shown to have a more rapid rate of absorption compared with ibuprofen 200 mg tablets. Ibuprofen liquigels have a kinetic profile similar to ibuprofen suspension, with both a higher Cmaxand an earlier tmaxthan any solid tablet. The objective of this single‐dose, double‐blind, triple‐dummy, parallel‐group study was to assess the time to onset of relief and overall analgesic efficacy of liquigel ibuprofen 400 mg, ketoprofen 25 mg compared with acetaminophen 1000 mg, and placebo in 239 patients with moderate or severe pain following third molar extractions. Treatments were compared over 6 hours using standard scales for pain intensity and relief and stopwatch onset of meaningful relief. All active treatments provided meaningful relief significantly faster compared with placebo. Ibuprofen provided significantly faster relief compared with acetaminophen and ketoprofen. By the end of the study (6 h), onset of meaningful relief was achieved by 36%, 99%, 96%, and 88% of the patients in the placebo, ketoprofen, ibuprofen, and acetaminophen groups, respectively. The median times to onset of relief were > 6 hours for placebo, 25.5 minutes for ketoprofen, 24.2 minutes for ibuprofen, and 29.9 minutes for acetaminophen. In addition, both ibuprofen and ketoprofen showed statistical superiority over acetaminophen at earlier time points on the time‐effect curves for pain relief and pain intensity difference. Consistent results were seen with respect to the 6‐hour summary efficacy variables: the three active treatments were significantly better than placebo, and ibuprofen was significantly better than both acetaminophen and ketoprofen. Liquigel ibuprofen 400 mg was shown to provide faster relief and superior overall efficacy compared with ketoprofen 25 mg, acetaminophen 1000 mg, and placebo. No serious adverse effects were reported in this single‐dose study.
Transient Kinetic and Dynamic Interactions between Verapamil and Dofetilide, a Class III Antiarrhythmic
Authors: Johnson Brian F. , Cheng Shu‐Lin , Venitz Jurgen
Published: July 2003

Potential kinetic and dynamic interactions between the new class III antiarrhythmic dofetilide (D) and the calcium channel blocker verapamil (V) were determined in 12 young healthy male volunteers. A fixed sequence of V 80 mg tid, placebo, D 0.5 mg bid, and D + V was given as matching active and placebo capsules. In steady‐state conditions during combination treatment, a modest increase in mean (± SD) peak plasma concentration of dofetilide from 2.40 0.42 to 3.43 ± 0.71 ng·ml−1(43% increase, p < 0.1) was noted. During the combination period, for the first 4 hours, mean AUC values for D increased from 7.4 ± 1.0 (D alone) to 9.2 ± 1.4 ng·h·ml−1 (26% increase, p < 0.1). No other significant pharmacokinetic interaction was seen. These transient changes were concurrent with trends for a dynamic interaction. The maximal mean increase in QTc over steady‐state baseline values was 20 msec for D alone versus 26 msec during combination therapy. This relatively small interactive effect occurred only while peak plasma drug concentrations were developing at 1 to 3 hours after dosing and is probably caused by the known effect of verapamil to increase hepatic and portal blood flow. In view of this interaction and the relationship between dofetilide plasma concentration and torsade, verapamil is contraindicated in patients receiving dofetilide.
Pharmacokinetics and Tolerability of Buspirone during Oral Administration to Children and Adolescents with Anxiety Disorder and Normal Healthy Adults
Authors: Salazar Daniel E. , Frackiewicz Edyta J. , Dockens Randy , Kollia Georgia , Fulmor I. Edgar , Tigel Phillip D. , Uderman Howard D. , Shiovitz Thomas M. , Sramek John J. , Cutler Neal R.
Published: July 2003

A 21‐day, open‐label, multisite, dose escalation study comprising three demographic groups (children, adolescents, and adults) was performed to determine the pharmacokinetics and tolerability of orally administered buspirone. Thirteen children and 12 adolescents with anxiety disorder and 14 normal healthy adults were escalated from 5 to 30 mg buspirone bid over the 3‐week study. Pharmacokinetic analysis revealed that buspirone was rapidly absorbed in all study groups, reaching peak levels at about 1 hour after administration. Peak plasma buspirone concentrations (Cmax) were highest in children and lowest in adults at all three dose levels (7.5, 15, 30 mg bid). However, 1‐pyrimidinylpiperazine (1‐PP), the primary metabolite of buspirone, exhibited a different plasma concentration‐time profile; Cmax was significantly higher in children than in either adolescents or adults at all concentrations. In addition, TAUC0‐T for 1‐PP was significantly higher in the children cohort relative to adolescents and adults. Buspirone was generally safe and well tolerated at doses up to 30mgbid in adolescents and adults and most of the children. The most frequently reported adverse events in children and adolescents were lightheadedness (68%), headache (48%), and dyspepsia (20%); 2 children withdrew from the study at the higher doses (15 mg and 30 mg bid) due to adverse effects. In adults, the most common adverse effect was somnolence (21.4%); lightheadedness, nausea, vomiting, and diarrhea were also reported, although these were mild in intensity.