Effect of Replicate Design on Drug
Variability and Bioequivalence in Humans |
Naji M. Najib1, Isam Salem1 and Nasir M. Idkaidek2* |
| 1International Pharmaceutical Research Center (IPRC), Amman, JORDAN |
| 2College of Pharmacy, Petra University, Amman, JORDAN |
| *Corresponding author: |
Dr. Nasir M. Idkaidek,
College of Pharmacy, Petra
University,
Amman, JORDAN,
E-mail : nidkaidek@uop.edu.jo |
|
| Received November 05, 2009; Accepted December 13, 2009; Published
December 13, 2009 |
Citation: Najib NM, Salem I, Idkaidek NM (2009) Effect of Replicate
Design on Drug Variability and Bioequivalence in Humans. J Bioanal
Biomed 1: 014-016. doi:10.4172/1948-593X.1000003 |
|
Copyright:© 2009 Najib NM, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are credited. |
Abstract |
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
(AUC0-t) and maximum concentration (Cmax)
were calculated by non-compartmental analysis using
Kinetica program V 4.2 using all phases. The 90 % confidence
intervals for log-transformed AUC0-t and Cmax 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 AUC0-t and Cmax
passed the 80-125 % limit range in both drugs for all phase
combinations, even though Cmax variability was shown high
for clavulanic acid. However, individual bioequivalence
was shown for AUC and not shown for Cmax 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%. |
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