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1. Curr Drug Metab. 2012 Mar 22. [Epub ahead of print]

Sex Differences in the Clearance of CYP3A4 Substrates: Exploring Possible Reasons
for the Substrate Dependency and Lack of Consensus.

Chetty M, Mattison D, Rostami-Hodjegan A.

Simcyp Limited, Blades Enterprise Centre, John Street, Sheffield S2 4SU, UK.
m.chetty@simcyp.com.

Sex differences in the clearance of substrates of Cytochrome P4503A (CYP3A4) have
been reported frequently although there has been no consensus on reasons for
variation in observations amongst drugs which are seemingly all dependent on this
enzyme for their metabolism. Moreover, these observations could not be replicated
in all studies even when investigating the same drugs. Differing study designs
and inadequate power to identify the sex differences may explain the conflicting
reports. The aim of the current study was to use in vitro data on a number of
CYP3A4 substrates to develop mechanistic population pharmacokinetic models which
are capable of integrating various attributes of drugs and estimating the
statistical power of in vivo studies designed to discern sex differences in the
clearance of CYP3A4 substrates. Midazolam, triazolam, alprazolam, nifedipine and
zolpidem were selected as test substrates. These compounds are predominantly
metabolised by CYP3A4, unaffected by p-glycoprotein and have abundant clinical
studies which can be used for validation purposes. Simulated apparent clearance,
obtained by use of the Simcyp® Population-Based Simulator and in vitro in vivo
extrapolation (IVIVE) techniques, was compared in males and females after
correcting for weight (CL/wt) in 1560 trials. Results suggested that about 105
subjects per study are required for an 80% probability of identifying a higher
CL/wt in females with alprazolam, while the corresponding numbers for a similar
power were 120, about 150 and 300 for nifedipine, triazolam and oral midazolam,
respectively. The results were consistent with outcomes in published clinical
studies and support the view that many of the published studies have inadequate
power to detect these sex differences in drug clearance, thereby contributing to
the lack of consensus on this subject.

PMID: 22452452 [PubMed - as supplied by publisher]