Robert D. Faulkner

Pharmacokinetic profile of cefixime in man

Cefixime is an orally absorbed third generation cephalosporin with a broad spectrum of activity against Gram-positive and Gram-negative bacteria and is highly resistant to beta-lactamase degradation. In general serum and urinary concentrations of cefixime achieved after recommended daily doses are well above the minimal inhibitory concentrations at 90% for indicated microorganisms. The pharmacokinetics of cefixime were determined in adult and pediatric subjects. In general the half-life of the drug is about 3 to 4 hours and is not dependent on dose. The drug is not extensively bound to serum proteins; the free fraction is about 31% and is concentration-independent. The absolute bioavailability, based on comparisons of area under the serum concentration-time curve values after 200-mg intravenous, 200-mg oral solution, and 200- and 400-mg capsule doses, ranged from 40 to 52%, showing a comparable bioavailability for cefixime at single 200- and 400-mg oral doses. In a dose proportionality study, over an oral dose range of 200 to 2000 mg, peak serum concentration (Cmax) and area under the concentration-time values increased linearly but were not directly proportional with dose. Upon multiple dosing for 2 weeks on a 400-mg daily or 200-mg twice a day regimen, serum concentrations and urinary recovery of unchanged drug were similar for each group, and there was no drug accumulation. Peak serum concentration and area under the concentration-time curve values after a 400-mg dose were almost double those after a 200-mg dose. All formulations of cefixime were bioequivalent to an oral reference solution at doses of 200 and 400 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of cefixime in the fasted and fed state

SummaryTwenty healthy adult volunteers received single 400 mg oral doses of cefixime in an open, randomized, crossover study, administered twice in the fasted state and twice with a standard breakfast. The study design allowed both an evaluation of a potential food effect and also an analysis of both intrasubject and intersubject variability in the fasted and fed state.There was a small but significantly longer (∼1 h) time to peak concentration when the drug was given with food. Peak serum concentrations, area under the curve, and 24 h urinary recovery values were unchanged in the fed and fasted states. The terminal elimination half-life of the drug given after a meal (3.6 h) was slightly longer than that observed after dosing in the fasting condition (3.5 h).The intrasubject and intersubject variabilities were less than 12% and 33% respectively, for both area under the curve and 24 h urinary recovery, and were virtually the same for the fasted and fed occasions. Therefore, the drug may be administered with or without food.

Pharmacokinetics of Cefixime After Once‐a‐Day and Twice‐a‐Day Dosing to Steady State

The pharmacokinetics of cefixime (CL 284,635; FK027), a new orally active broad‐spectrum cephalosporin, were determined in 26 healthy volunteers, after multiple 200‐mg twice‐a‐day (group 1; N = 13) or 400‐mg once‐a‐day (group 2; N = 13) dosing for 15 days. On study days 1, 8, and 15, mean peak serum concentrations (Cmax) were 1.67, 1.75, and 1.87 μg/mL, respectively, for group 1 and 2.76, 3.04, and 2.67, respectively, for group 2. Over the 15‐day period, mean trough serum concentrations were, on average, 0.40 and 0.08 μg/mL for groups 1 and 2, respectively. Comparison (ANOVA) of serum and urinary excretion pharmacokinetic parameters for cefixime on days 1, 8, and 15 found no significant (P > .05) differences for either group except for a small but significantly (P < .05) earlier time to reach Cmax and higher renal clearance on days 8 and 15 in group 1. These differences, however, are not clinically significant. On study days 1, 8, and 15, mean Cmax and AUC0‐r values for Group 2 were about 1.5 to 2.2 time those for Group 1. Urinary excretion of cefixime accounted for 11.9 to 14.5% and 9.9 to 12.4% of the dose in groups 1 and 2, respectively, over the 15‐day study. Overall, there was no accumulation of cefixime in serum or urine nor was there a reduction in serum concentrations or urinary amounts over the 15‐day dosing period when the drug was given either as a 200‐mg twice‐a‐day or 400‐mg once‐a‐day dosing regimen.

Pharmacokinetics of Tazobactam M1 Metabolite After Administration of Piperacillin/Tazobactam in Subjects with Renal Impairment

Tazobactam is a new derivative of penicillinic acid sulfone, which functions as an irreversible inhibitor of many β‐lactamases. The disposition of tazobactam M1 metabolite after intravenous (IV) infusion of 3 g of piperacillin/0.375 g of tazobactam was evaluated in 26 subjects with various degrees of renal impairment. Participants in the study were 18 subjects with creatinine clearances (ClCR) ranging from 7.4–41.8 mL/min, 4 subjects maintained on continuous ambulatory peritoneal dialysis (CAPD), and 4 subjects undergoing chronic hemodialysis (HD). The pharmacokinetic parameters of piperacillin and tazobactam were evaluated and were similar to previous reports. Tazobactam M1 metabolite maximum plasma concentration increased as renal function declined. The terminal elimination half‐life and area under the plasma concentration—time curve of the tazobactam M1 metabolite increased as renal function declined. The mean rate of recovery of the tazobactam M1 metabolite in hemodialysate during a 3‐ to 4.2‐hour HD session 1 hour after the IV infusion of piperacillin/tazobactam was 25.3%. However, when HD was performed at 36–48 hours after the IV infusion, 57.6% of the tazobactam dose was recovered as M1 metabolite, suggesting further conversion of tazobactam to M1 metabolite. Peritoneal dialysis removed 15.8% (n=2) of the tazobactam dose as the M1 metabolite. Using a dose of 3 g of piperacillin/0.375 g of tazobactam, the predicted maximum steady‐state plasma concentrations of the tazobactam M1 metabolite are 14.6 μg/mL, 34.8 μg/mL, and 48.8 μg/mL for subjects with ClCR 20–40 mL/min (every 6 hour dosing), ClCR <20 mL/min (every 8 hour dosing), and on CAPD (every 12 hour dosing), respectively.

Bioequivalency of solid oral dosage forms of cefixime

Abstract A study was performed in 24 healthy subjects to determine whether tablet and capsule formulations of cefixime (CL 284,635; FK027), a new oral cephalosporin, given as a single 400 mg dose, were bioequivalent to one another and to a reference oral solution. Mean values of C max in serum were 3.87, 3.39, and 3.82 μg/ml after tablet, capsule and solution doses, respectively. Comparison (ANOVA) of the pharmacokinetic parameters showed significantly ( P 0 → ∞ and C max values for the capsule than for the tablet; however, the mean differences were less than 16%. All pharmacokinetic parameters for the tablet, except for a significantly larger MRT ni and t max , were comparable to those for the solution. The bioavailability of cefixime based on AUC 0 → ∞ and 24-h urinary recovery data from the tablet dosage form was slightly better (mean differences 14–16%) than from the capsule and virtually identical to that after the oral solution. The statistical power of the study was greater than 90% to detect a difference in AUC 0 → ∞ values of 20%. Overall, based on AUC 0 → ∞ comparisons, the results show that the tablet, capsule and oral reference solution are bioequivalent to one another.

IMPLEMENTATION OF AN EFFECTIVE PHARMACOKINETICS RESEARCH PROGRAM IN INDUSTRY

Over the past decade the application of pharmacokinetic data in drug development has gradually increased. Today it is well recognized that successful drug development programs include meaningful supportive pharmacokinetic data. An effective pharmacokinetic program begins at the preclinical phase with well defined objectives to support pharmacology/toxicology programs, to determine effective/toxic blood concentration ranges and to help in expediting early phase I studies in man. The clinical pharmacokinetic program may be classified as follows: i) pharmacokinetics during safety and tolerance studies in man to determine key pharmacokinetic parameters including linearity over the utilized dose range, and related effective and toxic blood concentrations; ii) pivotal pharmacokinetic studies to determine metabolism profile and major active/inactive metabolite(s) in man, extent of first-pass metabolism, absolute and/or relative bioavailability, effect of food on absorption, dose proportionality, route and mechanism of elimination, bioequivalency of final dosage forms and to establish therapeutic dosing regimens; and iii) studies supporting labeling to determine pharmacokinetics in special populations, effect of disease states and interactions with concomitantly administered drugs. A successful pharmacokinetic program is done prospectively to support the design of safety evaluation studies, to assist in expediting the Phase I/II programs, and to facilitate the Phase III trials in patients.