Paul Glue

Pegylated interferon‐α2b: Pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data

The objectives of this study were to assess the safety, pharmacokinetic and pharmacodynamic profiles, and antiviral efficacy of pegylated interferon‐α2b monotherapy in patients with chronic hepatitis C.

Ribavirin uptake by human erythrocytes and the involvement of nitrobenzylthioinosine-sensitive (es)-nucleoside transporters

The major toxicity associated with oral therapy with ribavirin is anaemia, which has been postulated to occur as a result of accumulation of ribavirin triphosphate interfering with erythrocyte respiration. The objective of this study was to determine the mechanism by which ribavirin enters into erythrocytes. Entry into human erythrocytes was examined by measuring influx rates of [3H]‐ribavirin alone and with the inhibitor nitrobenzylthioinosine (NBMPR), and by investigating the inhibitory effects of nucleoside and nucleobase permeants on ribavirin transport, by use of inhibitor oil‐stop methods. Transport mechanisms were further characterized by assessment of substrates to cause countertransport of ribavirin in preloaded erythrocytes, and by measuring the effects of ribavirin on [3H]‐NBMPR binding to erythrocyte membranes. Human erythrocytes had a saturable influx mechanism for ribavirin (Km at 22°C of 440±100 μM) which was inhibited by nanomolar concentrations of NBMPR (IC50 0.99±0.15 nM). Nucleosides also inhibited the influx of ribavirin (adenosine more effective than uridine) but the nucleobases hypoxanthine and adenine had no effect. In addition, uridine caused the countertransport of ribavirin in human erythrocytes. Entry of ribavirin into horse erythrocytes, a cell type that lacks the NBMPR‐sensitive (es) nucleoside transporter, proceeded slowly and via a pathway that was resistant to NBMPR inhibition. Ribavirin was a competitive inhibitor of adenosine influx (mean Ki 0.48±0.14 mM) and also inhibited NBMPR binding to erythrocyte membranes (mean Ki 2.2±0.39 mM). These data indicate that ribavirin is a transported permeant for the es nucleoside transporter of human erythrocytes. There was no evidence for ribavirin entering cells via a nucleobase transporter.

Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive

The effects of felbamate on the pharmacokinetics of a low‐dose combination oral contraceptive containing 30 μg ethinyl estradiol and 75 μg gestodene were assessed in a randomized, double‐blind, placebo‐controlled parallel‐group study in healthy premenopausal female volunteers established in a regimen of oral contraceptive use. They received either placebo or 2400 mg/day felbamate from midcycle (day 15) to midcycle (day 14) of two consecutive oral contraceptive cycles (months 1 and 2). Pharmacokinetic assessments of ethinyl estradiol and gestodene were performed on day 14 of both cycles. To determine whether ovulation occurred, plasma progesterone and urinary luteinizing hormone levels were measured, and diaries recording vaginal bleeding were kept. Felbamate treatment resulted in a significant 42% decrease in gestodene area under the plasma concentration‐time curve (0 to 24 hours) (p = 0.018) compared with baseline, whereas a minor but not clinically relevant effect was observed on the pharmacokinetic parameters of ethinyl estradiol. There were no changes in the pharmacokinetics of ethinyl estradiol or gestodene after placebo treatment. No volunteer showed hormonal evidence of ovulation; however, one volunteer reported the onset of intermenstrual bleeding during felbamate treatment. Because of the effect of felbamate on the pharmacokinetics of gestodene and the report of intermenstrual bleeding, it is possible that the contraceptive efficacy of low‐dose combination oral contraceptives may be adversely affected during felbamate treatment.

Ribavirin dosing in chronic hepatitis C: Application of population pharmacokinetic-pharmacodynamic models

Combination therapy of ribavirin with interferon alfa‐2b and pegylated interferon alfa‐2b is currently approved for the treatment of chronic hepatitis C. Approved ribavirin dosages vary from a fixed dosage of 800 mg/d to as much as 1200 mg/d on the basis of body weight.

Effects of felbamate on the pharmacokinetics of phenobarbital

The effects of felbamate on the pharmacokinetics of phenobarbital and one of its main metabolites, parahydroxyphenobarbital, were assessed in a parallel‐group, placebo‐controlled, double‐blind study, in 24 healthy volunteers. Pharmacokinetic parameters of phenobarbital and parahydroxyphenobarbital were determined from plasma and urine samples obtained after 28 days of daily administration of 100 mg phenobarbital and after a further 9 days of phenobarbital plus 2400 mg/day felbamate or placebo. Felbamate increased phenobarbital values for area under the plasma concentration‐time curve from 0 to 24 hours and maximum concentration by 22% and 24%, respectively, whereas placebo had no effect. This increase was caused by a reduction in parahydroxylation of phenobarbital and possibly through effects on other metabolic pathways. Because felbamate inhibits the S‐mephenytoin hydroxylase (CYP2C19) isozyme in vitro, it appears that phenobarbital hydroxylation is mediated in part by this isozyme.

Population pharmacokinetic analysis of pegylated interferon alfa‐2b and interferon alfa‐2b in patients with chronic hepatitis C

This study quantified pharmacokinetic changes in pegylated and nonpegylated interferon alfa‐2b during 48 weeks of treatment and the influences of covariates on the basis of sparsely sampled serum concentrations and activity values. Possible relationships between pharmacokinetic and pharmacodynamic variables were investigated.

Pharmacokinetic interactions with felbamate. In vitro-in vivo correlation.

SummaryThis article provides an analysis of the degree of agreement between in vivo interaction studies performed in patients with epilepsy and healthy individuals, and in vitro studies which identified the cytochromes P450 (CYP) inhibited by felbamate and those involved in its metabolism. In vitro studies show that felbamate is a substrate for CYP3A4 and CYP2E1. Compounds which induce CYP3A4 (e.g. carbamazepine, phenytoin and phenobarbital) increase felbamate clearance. However, the CYP3A4 inhibitors gestodene, ethinyl estradiol and erythromycin have little or no effect on felbamate trough plasma concentrations, consistent with the fact that the pathway is relatively minor for felbamate under normal (non-induced) conditions.Felbamate has been shown in vitro to inhibit CYP2C19, which would account for its effect on phenytoin clearance, and it has been postulated that this could be the mechanism underlying the reduced clearance of phenobarbital by felbamate.Although not yet examined in vitro, felbamate appears to induce the activity of CYP3A4, which would account for it reducing plasma concentrations of carbamazepine or the progestin gestodene. Interactions involving felbamate and non-CYP450-mediated metabolic pathways have also been addressed in clinical studies. The reduction in valproic acid (valproate sodium) clearance by felbamate is through the inhibition of β-oxidation.No clinically relevant pharmacokinetic interactions were noted between felbamate and lamotrigine, clonazepam, vigabatrin, nor the active monohydroxy metabolite of oxcarbazepine. Information on the mechanisms underlying felbamate’s drug: drug interaction profile permits predictions to be made concerning the likelihood of interactions with other compounds.

Cytochrome P450 Enzymes and Drug Metabolism—Basic Concepts and Methods of Assessment

Abstract1. The cytochrome P450 enzyme family is one of the major drug metabolizing systems in man.2. Factors such as age, gender, race, environment, and drug treatment may have considerable influence on the activity of these enzymes.3. There are now well-established in vitro techniques for assessing the role of specific cytochrome P450 enzymes in the metabolism of drugs, as well as the inhibitory or inducing effects of drugs on enzyme activity. In vitro data have been utilized to predict clinical outcomes (i.e., pharmacokinetic interactions), with close correlations between in vitro and in vivo data.4. This information can be of considerable practical assistance to clinicians, to help with rational prescribing or to prevent or minimize the potential for drug interactions.

Oral Bioavailability of Desloratadine Is Unaffected by Food

AbstractObjective: To determine the effect of coadministration of food on the bioavailability of oral desloratadine. Design: A randomised, open-label, single dose crossover study in which healthy adults received a single, oral dose of desloratadine 7.5mg, 50% greater than the recommended dose of 5mg, under fed or fasted conditions and were then crossed over to receive the other treatment regimen. Participants: 18 healthy volunteers (11 men, 7 women) aged from 18 to 43 (mean 29) years and weighing 54 to 104 (mean 76.4) kg were enrolled and completed this study. Main outcome measures: Cmax, AUCs and AUC∞. Results: Maximum mean plasma concentration (Cmax) was 3.53 μg/L in fed compared with 3.30 μg/L in fasted participants. Area under the plasma concentration-time curve from time 0 to time of final quantifiable sample (AUCs) mean values were 61.0 μg/L · h in fed and 61.9 μg/L · h in fasted participants. Fed individuals had mean AUC extrapolated to infinity (AUC∞) of 62.5 μg/L μ h compared with 63.5 μg/L · h in fasted participants. None of these differences between the fed and fasted state was statistically significant. The most frequently reported adverse event was headache. There were no statistically significant changes in ECG parameters. Conclusion: The results of this study indicate that food has no effect on the oral bioavailability of a single oral dose of desloratadine 7.5mg.

Psychiatry, psychopharmacology and P-450s

The cytochrome P‐450 enzyme family is one of the major drug metabolizing systems in man. Over the last decade, advances in molecular biology, in vitro and clinical pharmacology techniques have increased our understanding of their role in the metabolism of psychotropic drugs, the effects of psychotropics on enzyme inhibition and induction, and how the pharmacokinetics of psychotropics are affected by changes in enzyme activity. There is also greater awareness of the influence of factors such as age, gender, race and environment on enzyme activity. This information can be of considerable assistance to psychiatrists, to help with rational prescribing, or to prevent or minimize the potential for drug interactions.