Evaluation of bioequivalence of highly variable drugs using clinical trial simulations. II: Comparison of single and multiple-dose trials using AUC and Cmax.
OBJECTIVE
Evaluating of the effects of high intrasubject variability in clearance (CL) and volume of distribution (V), on 90% confidence intervals (CIs) for AUC (Area Under the concentration Curve) in single and multiple-dose bioequivalence studies. The main methodology was Monte Carlo simulation, and we also used deterministic simulation, and examination of clinical trials. The results are compared with those previously observed for Cmax (maximum concentration.)


METHODS
The time course of drug concentration in plasma was simulated using a one-compartment model with log-normal statistical distributions of intersubject and intrasubject variabilities in the pharmacokinetic parameters. Both immediate-release and prolonged-release products were simulated using several levels of intrasubject variability in single-dose and multiple-dose studies. Simulations of 2000 clinical bioequivalence trials per condition (138 conditions) with 30 subjects in each crossover trial were carried out. Simulated data were compared with data from actual bioequivalence trials.


RESULTS
The current simulations for AUC show similar probabilities of failure for single-dose and multiple-dose bioequivalence studies, even with differences in the rate of absorption or fraction absorbed. AUC values from prolonged-release scenario studies are more sensitive to changes in the first order absorption rate constant ka, and to variability in CL and V than AUC from studies of immediate-release studies.


CONCLUSIONS
We showed that multiple-dose designs for highly variable drugs do not always reduce intrasubject variability in either AUC or Cmax, although the behavior of AUC differs from Cmax. Single dose AUC to the last quantifiable concentration was more reliable than either single dose AUC extrapolated to infinity, or multiple dose AUC during a steady-state interval. Multiple-dose designs may not be the best solution for assessing bioequivalence of highly variable drugs.
el-Tahtawy
A A
AA
Food and Drug Administration, Center for Drug Evaluation and Research, Rockville, Maryland 20857, USA. Eltahtawya@cder.fda.gov
Tozer
T N
TN
Harrison
F
F
Lesko
L
L
Williams
R
R
D019540:Area Under Curve; D003198:Computer Simulation; D004338:Drug Combinations; D008657:Metabolic Clearance Rate; D008956:Models, Chemical; D009010:Monte Carlo Method; D010599:Pharmacokinetics; D013810:Therapeutic Equivalency
D004338:Drug Combinations