Determination of rifampicin bioequivalence in a three-drug FDC by WHO and indian protocols: effect of sampling schedule and size.

SETTING

To promote the quality assurance of fixed-dose combination (FDC) formulations, the World Health Organization (WHO) has prepared a convenient simplified protocol for the determination of rifampicin (RMP) bioequivalence. During the development of this protocol, it was proved that sampling time up to 8 h can determine the rate and extent of RMP absorption. However, this protocol utilises 20 volunteers in contrast to other local regulatory requirements of a minimum of 12 volunteers. The different sample sizes utilised in these protocols may affect the sensitivity of the bioequivalence outcome.

OBJECTIVE

To determine the effect of sampling size and schedule on RMP bioequivalence when two different protocols are used.

DESIGN

A bioequivalence trial was conducted with a study design of 20 volunteers and 24 h sampling time, which fulfils the requirements of both the WHO and Indian regulatory protocols. Pharmacokinetic and statistical analysis was done by stepwise reduction in sample size and schedule.

RESULT

Bioequivalence limits of RMP were unaffected by a reduced sample size of 12 volunteers and 8 h sampling time.

CONCLUSION

Minimising sample size after validation for borderline and poor quality FDC formulations can further reduce the cost of conducting bioequivalence trials.