Karl A. DeSante

Pharmacokinetic profile of loracarbef

Loracarbef, the first β-lactam antibiotic of the carbacephem class to undergo clinical evaluation, has been the subject of extensive clinical pharmacology studies. Loracarbef is well absorbed: virtually all of an orally administered dose is excreted in the urine unchanged. Following administration of a 100 mg capsule to adults twice a day for 10 days, no accumulation of drug is noted. In one study in children, following the administration of 15 mg/kg of loracarbef suspension, the mean maximum plasma concentration (Cmax) was 20.3 μg/mL. In adults, the Cmax following administration of the suspension or solution formulations is higher than that achieved following administration of the capsule formulation, and the time to reach peak concentration (Tmax) is increased when loracarbef is administered as a capsule: however, the area under the curve, plasma half-life, and percentage of oral dose excreted in the urine are comparable among all formulations. The ingestion of food decreases the Cmax and delays the Tmax compared with the fasting state. The pharmacokinetic profile of loracarbef in adults is comparable with that in children or the elderly. Because loracarbef is eliminated primarily by the kidney, dosage must be reduced in patients with moderate-to-severe renal insufficiency. Loracarbef achieves middle-ear and interstitial-fluid levels that generally exceed the minimum inhibitory concentrations for common bacterial pathogens. Loracarbef possesses a pharmacokinetic profile consistent with the efficacy and safety profile documented in controlled clinical trials.

Pharmacokinetics, Safety, and Tolerability of Atomoxetine and Effect of CYP2D6*10/*10 Genotype in Healthy Japanese Men

Atomoxetine is a cytochrome P4502D6 (CYP2D6) substrate. The reduced‐activity CYP2D6*10 allele is particularly prevalent in the Japanese population and may contribute to known ethnic differences in CYP2D6 metabolic capacity. The purpose of this study was to examine atomoxetine pharmacokinetics, safety, tolerability, and the effect of the CYP2D6*10/*10 genotype after single‐stepped dosing (10, 40, 90, or 120 mg) and at steady state (40 or 60 mg twice a day for 7 days) in 49 healthy Japanese adult men. Dose proportionality was shown and tolerability confirmed at all doses studied. Comparison of pharmacokinetics, safety, and tolerability between Japanese and US subjects showed no clinically meaningful ethnic differences. The CYP2D6*10/*10 subjects had 2.1‐ to 2.2‐fold and 1.8‐fold higher area under the plasma concentration—time curve values relative to the CYP2D6*1/*1 and *1/*2 subjects and the CYP2D6*1/*10 and *2/*10 subjects, respectively. The adverse events reported by CYP2D6*10/*10 subjects were indistinguishable from those of other Japanese participants. The higher mean exposure in CYP2D6*10/*10 subjects is not expected to be clinically significant.

Changes in the steady-state pharmacokinetics of theophylline during treatment with dirithromycin

The steady‐state plasma concentrations and pharmacokinetic characteristics of theophylline were studied during intermittent treatment with dirithromycin. The addition of dirithromycin (500 mg orally once daily at 7:00 am) to a sustained‐release theophylline dosing regimen (200 mg every 12 hours) elicited small changes in the steady‐state pharmacokinetics of theophylline. Mean steady‐state plasma theophylline trough concentrations (Cmin) were invariant before, during, and after dirithromycin treatment; however, mean average steady‐state plasma theophylline concentrations (Cav) declined by 18% during dirithromycin treatment (P < .05), and mean peak plasma concentrations (Css,max) declined by 26% (P < .01). Theophylline clearance (CL/F) exhibited an increase of comparable magnitude during dirithromycin treatment, although the increase in CL/F was not statistically significant (.05 < P < .1). Dirithromycin treatment alters the steady‐state pharmacokinetics of theophylline; however, the magnitude of the changes is small and is not likely to modify treatment outcomes.

Effect of Dirithromycin on Human CYP3A In Vitro and on Pharmacokinetics and Pharmacodynamics of Terfenadine In Vivo

Terfenadine is metabolized by the cytochrome P‐450 3A subfamily of enzymes (CYP3A). Certain macrolide antibiotic agents inhibit CYP3A and, when coadministered with terfenadine, result in a drug interaction. The authors compared the abilities of dirithromycin (a new macrolide antibiotic agent), its major metabolite erythromycylamine, and the known CYP3A substrate terfenadine to inhibit CYP3A in vitro. The hydroxylation of midazolam in human liver microsomes was used as a probe for CYP3A activity. Dirithromycin and erythromycylamine were low affinity inhibitors of CYP3A (inhibitory binding affinities of 493 μmol/L and 701 μmol/L, respectively); conversely, terfenadine was a moderate affinity inhibitor (inhibitory binding affinity of 28 μmol/L). Based on these data, the authors tested the hypothesis that dirithromycin would not interact with terfenadine in humans. Six healthy men received terfenadine alone (60 mg twice daily) for 8 days, after which dirithromycin (500 mg once daily) was added to the terfenadine regimen for an additional 10 days. The pharmacokinetics of terfenadine (and its acid metabolite) and the QTc interval were measured during both treatments, and it was found that neither parameter was affected. In this study, dirithromycin was found to have low affinity for human CYP3A in vitro, which is in accordance with the studys finding that in vivo dirithromycin has no major effect on the metabolism of the CYP3A substrate terfenadine in humans.

Tmax: an unconfounded metric for rate of absorption in single dose bioequivalence studies.

AbstractPurpose. While peak drug concentration (Cmax) is recognized to be contaminated by the extent of absorption, it has long served as the indicator of change in absorption rate in bioequivalence studies. This concentration measure per se is a measure of extreme drug exposure, not absorption rate. This paper redirects attention to Tmax as the absorption rate variable. Methods. We show that the time to peak measure (Tmax), if obtained from equally spaced sampling times during the suspected absorption phase, defines a count process which encapsulates the rate of absorption. Furthermore such count data appear to follow the single parameter Poisson distribution which characterizes the rate of many a discrete process, and which therefore supplies the proper theoretical basis to compare two or more formulations for differences in the rate of absorption. This paper urges limiting the use of peak height measures based on Cmax to evaluate only for dose-dumping, a legitimate safety concern with, any formulation. These principles and techniques are illustrated by a bioequivalence study in which two test suspensions are compared to a reference formulation. Results. Appropriate statistical evaluation of absorption rate via Tmax supports bioequivalence, whereas the customary analysis with Cmax leads to rejection of bioequivalence. This suggests that the inappropriate use of Cmax as a surrogate metric for absorption rate contributes to the unpredictable and uncertain outcome in bioequivalence evaluation today.

Clinical pharmacokinetics of Pinacidil, a potassium channel opener, in hypertension

Pinacidil is a potassium channel opener that decreases blood pressure by reducing peripheral arterial resistance. In two multicenter trials, we studied the concentrations and apparent clearance of pinacidil (406 patients) and concentrations of its pyridyl‐N‐oxide metabolite (147 patients). Responding patients had plasma samples collected hourly for 12 hours on 2 occasions after weeks to months of treatment. Pinacidil dose was titrated from 12.5 to 75 mg b.i.d. The peak concentration of pinacidil and N‐oxide and the area under the concentration‐time curve (AUC) were proportional to the dose of pinacidil, with an average pinacidil concentration of 268 μg/L (1.02 μM) and N‐oxide concentration of 172 μg/L (0.65 μM) for every 1 mg/kg pinacidil administered. Clearance of pinacidil (Clp = Dose/AUC) was 31 L/hr in patients younger than 45 years and 27 L/hr in those older than 60. Clp was significantly smaller in white patients compared with other races (Clp = 28 vs. 34 L/hr). Clp was significantly less in patients taking hydrochlorothiazide (27 vs. 31 L/hr) and greater in smokers (33 vs. 29 L/hr). Concomitant propranolol use did not influence Clp.

Effects of renal dysfunction on the pharmacokinetics of loracarbef

Loracarbef, the first carbacephem antibiotic to undergo clinical development, is excreted primarily unchanged in the urine (>90%). Data analyzed from subjects with various degrees of renal dysfunction who were given single oral doses of loracarbef indicated a linear relationship between creatinine clearance (CLCR) and plasma clearance [CLp(L/hr) = 0.106 CLCR(ml/min/1.73 m2)]. The mean area under the plasma concentration‐time curve in normal subjects and in patients with severe renal insufficiency (no dialysis/receiving dialysis) was 32 μg · hr/ml and 1085 μg · hr/ml/103 μg · hr/ml, respectively. Therefore, for individuals with moderate renal insufficiency (CLCR, 10 to 49 ml/min/1.73 m2), the dose should be halved or the dosing interval doubled; patients with severe renal insufficiency who are not receiving dialysis should be treated with the normal dose given once every 3 to 5 days. Loracarbef is readily cleared from plasma by hemodialysis; dosing should be repeated after a hemodialysis treatment.

Influence of Sulfaethidole on the Human Pharmacokinetics of Dicloxacillin

In a five-patient crossover study, serum levels of dicloxacillin after intravenous administration of dicloxacillin in the absence and presence of sulfaethiodole were measured. Significantly greater serum concentrations of dicloxacillin were noted when dicloxacillin was administered with sulfaethidole. Pharmacokinetic evaluation of the data suggests that the higher serum concentrations were primarily the result of changes in the extravascular distribution for dicloxacillin in the presence of sulfaethidole. Although examination of the distribution rate constants for dicloxacillin in a two-compartment open model would suggest a lowering of serum concentrations, the experimental data clearly indicate that the serum and tissue compartment dicloxacillin concentrations increased in the presence of sulfaethiodle, indicating that protein binding in the central as well as extravascular compartments could be affected by sulfaethidole.