Lack of correlation between in vitro inhibition of CYP3A-mediated metabolism by a PPAR-gamma agonist and its effect on the clinical pharmacokinetics of midazolam, an in vivo probe of CYP3A activity

RG 12525 (2-[[4-[[2-1H-tetrazole-5-ylmethyl)phenyl]methoxy]phenoxy]methyl] quinolone) is a novel peroxisome proliferator-activated receptor gamma (PPA R-gamma) agonist. In vitro microsomal inhibition assays indicated that AG 1 2525 is a potent inhibitor of CYP3A4, with a K-i value of 0.5 muM. With the conservative assumption that the fetal plasma concentration of drug was av ailable to metabolic enzymes following RG 12525 oral administration, marked inhibition of CYP3A4 was expected to substantially reduce the systemic cle arance of compounds metabolized by this enzyme. The possibility also existe d for inhibition of intestinal and hepatic CYP3A4 by RG 12525 to reduce "fi rst-pass" metabolism and increase absolute bioavailability of CYP3A4 substr ates orally coadministered. Consequently, an in vivo drug-drug interaction study was performed to evaluate the effects of orally administered RG 12525 on in vivo CYP3A4 activity in healthy male subjects. The pharmacokinetics of oral midazolam, a probe for intestinal and hepatic CYP3A activity, was n ot influenced by either the low (100 mg qd for 4 days) or high (600 mg qd f or 4 days) RG 12525 dosing regimen despite the resulting total plasma conce ntrations of inhibitor that were well above in vitro K-i values. The point estimates and 90% confidence intervals for the ratios of mean midazolam AUC for subjects administered 100 mg RG 12525 (110.6; 98.7-124.1) and 600 mg R G 12525 (98.4; 84.4-114.7) versus midazolam alone were within 80% to 125%. To explain these results, factors that could limit the accuracy of in vitro models in predicting metabolic drug interactions, mainly the high degree o f RG 12525 protein binding (>99.9%), were considered. The lack of correlati on between the in vitro inhibition of CYP3A4 by RG 12525 and the inconseque ntial effects of this compound on midazolam pharmacokinetics accentuate the need to recognize factors other than plasma drug concentrations and potenc y of in vitro enzyme inhibition when extrapolating in vitro data to predict in vivo drug-drug interactions. Journal of Clinical Pharmacology, 2001;41: 305-316 (C) 2001 the American College of Clinical Pharmacology.