Robert E. Desjardins

Opportunities for Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development

Carl C. Peck, MD, William H. Barr, PharmD, PhD, Leslie Z. Benet, PhD, Jerry Collins, PhD, Robert E. Desjardins, MD, Daniel E. Furst, MD, John G. Harter, MD, Gerhard Levy, PharmD, Thomas Ludden, PhD, John H. Rodman, PharmD, Lilly Sanathanan, PhD, Jerome J. Schentag, Pharmfl, Vinod P. Shah, PhD, Lewis B. Sheiner, MD, Jerome P. Skelly, PhD, Donald R. Stanski, MD, Robert J. Temple, MD, C. T. Viswanathan, PhD, Judi Weissinger, PhD, and Avraham Yacobi, PhD

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.

Dose Proportionality of Bisoprolol Enantiomers in Humans After Oral Administration of the Racemate

Dose proportionality of racemic bisoprolol and the stereoselectivity of its enantiomers were studied after single oral dosing of 5 to 40 mg of bisoprolol hemifumarate in eight healthy male volunteers in an open‐label, randomized, four‐way cross‐over trial. There were dose‐proportional increases in mean peak plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) values for the racemate and the individual enantiomers. No statistically significant differences were detected between the mean half life (t1/2), Cmax, and time to reach Cmax (tmax) of the R‐ and S‐isomers at each of the four dose levels studied. These findings support dose proportionality and absence of stereoselective pharmacokinetics for bisoprolol in the dose range studied.

Opportunities for integration of pharmacokinetics, pharmacodynamics and toxicokinetics in rational drug development: Sponsored by the American Association of Pharmaceutical Scientists, U.S. Food and Drug Administration and American Society for Clinical Pharmacology and Therapeutics

Abstract This report derives from the conference on ‘The Integration of Pharmacokinetic, Pharmacodynamic and Toxicokinetic Principles in Rational Drug Development,’ held on April 24–26, 1991 in Arlington, VA. The conference was sponsored by the American Association of Pharmaceutical Scientists, U.S. Food and Drug Administration and American Society for Clinical Pharmacology and Therapeutics. The objectives of the conference were: (1) To identify the roles and the interrelationships between pharmacokinetics (PK), pharmacodynamics (PD) and toxicokinetics (TK) in the drug development process. (2) To evolve strategies for the effective application of the principles of pharmacokinetics, pharmacodynamics and toxicokinetics in drug development, including early clinical trials. (3) To prepare a report on the use of pharmacokinetics and pharmacodynamics in rational drug development as a basis for the development of future regulatory guidelines.

Importance of Oral Dosing Rate on the Hemodynamic and Pharmacokinetic Profile on Nilvadipine

Nilvadipine was administered as an oral solution formulation to 12 normotensive subjects in a three‐way randomized crossover study at at dose of 16 mg as three different dosing regimens: 1) as a single 16 mg dose, 2) as a 1.6 mg dose given hourly for 10 doses, and 3) as an initial dose of 4.8 mg, followed by 1.6 mg doses given every hour for seven additional doses. After each dose, clinical effects, hemodynamic changes and the pharmacokinetic profile of the drug were determined. The mean maximum changes in diastolic (DBP) and systolic (SBP) blood pressure and heart rate (HR) after dosing regimens 1, 2, and 3 were: −33, −13 and +46%; −17, −14 and +38%; and −24, −14 and +36%, respectively. There was a relationship between the changes in DBP and HR and plasma concentrations of nilvadipine only after dosing regimen 1. The effect‐concentration relationships were fit to a modified Emax model. There was no relationship between the change in SBP and plasma concentration after any of the dosing regimens. While there were no significant differences in the mean area under the plasma concentration‐time curve (AUC0→∞) between dosing regimens 2 (38.7 ng ṁ hr/mL) and 3 (42.1 ng ṁ hr/mL) (P > 0.05), the mean AUC0→∞ after regimen 1 (76.3 ng ṁ hr/mL) was significantly greater than after dosing regimens 2 or 3 (P < 0.05). The mean maximal plasma concentrations (Cmax) were 31.6, 1.3 and 6.3 ng/mL after dosing regimens 1, 2 and 3, respectively. Overall the results showed that nilvadipine caused changes in blood pressure and HR and that the largest changes were seen with dosing regimen 1, where peak plasma concentrations were greater than about 10 ng/mL.

Pharmacokinetics of Nilvadipine After Multiple Oral Dosing to Steady-State

AbstractForty-four healthy male volunteers were randomly assigned to receive one of four dosing regimens: placebo or a dose of 6, 8, 10 or 12 mg of nilvadipine administered at 0, 7 and 14 hr each day for 19 doses over seven days. There was a proportional relationship between the maximum plasma concentration of nilvadipine after the first dose and the last dose and the dose administered. There was also a proportional relationship between the area under the plasma concentration-time curve during the last dosing interval and the administered dose. Results showed that there was no accumulation of drug in plasma at steady-state. In addition, there was no dose-dependency in the oral clearance, elimination rate constant or terminal elimination half-life values. The pharmacokinetics of nilvadipine are linear upon multiple dosign over the dosing range studied

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.