title: Sex differences in the clearance of CYP3A4 substrates: exploring possible reasons for the substrate dependency and lack of consensus.
abstract: 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 metabolized 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.
authors.affiliation: Simcyp Limited, Blades Enterprise Centre, John Street, Sheffield S2 4SU, UK. m.chetty@simcyp.com
authors.forename: Manoranjenni
authors.initials: M
authors.lastname: Chetty
authors.forename: Donald
authors.initials: D
authors.lastname: Mattison
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
mesh_terms: D000328:Adult; D001569:Benzodiazepines / Q000493:pharmacokinetics*; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009543:Nifedipine / Q000493:pharmacokinetics*; D011725:Pyridines / Q000493:pharmacokinetics*; D012727:Sex Characteristics
chemical_list: D011725:Pyridines; D001569:Benzodiazepines; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009543:Nifedipine