Effect of Replicate Design on Drug Variability and Bioequivalence in Humans

The purpose of this study is to investigate the effect of using replicate design on the intra/inter subject variability and bioequivalence of drugs in healthy volunteers. Model drugs used for analysis were amoxicillin/clavulanic acid combination. 24 healthy subjects participated in this study using 4-phase replicate cross over design. Individual disposition kinetic parameters of areas under plasma concentrations (AUC 0-t ) and maximum concentration (C max ) were calculated by non-compartmental analysis using Kinetica program V 4.2 using all phases. The 90 % confidence intervals for log-transformed AUC 0-t and C max were calculated for phases I & II; then for phases I, II and III; and for phases I, II, III and IV respectively. The intra and inter-subject variability values did not show a trend to decrease by the increase in phases included in analysis in both drugs and for both parameters. In addition, the 90 % confidence intervals for log-transformed AUC 0-t and C max passed the 80-125 % limit range in both drugs for all phase combinations, even though C max variability was shown high for clavulanic acid. However, individual bioequivalence was shown for AUC and not shown for C max of both drugs. These results suggest not using replicate design as an approach to show the high inter/intra subject variability of highly variable drugs and hence justify wider acceptance limits of 75-133 % as recommended by the draft EMEA guideline. Literature information about drug high variability should be adequate to justify using wider acceptance limits of 75-133%. Effect of Replicate Design on Drug Variability and Bioequivalence in Humans Naji M. Najib, Isam Salem and Nasir M. Idkaidek*