Prediction of drug clearance in a smoking population: modeling the impact of variable cigarette consumption on the induction of CYP1A2

Abstract

To derive estimates of CYP1A2 abundance as a function of daily cigarette consumption and use these values to predict the clearances of CYP1A2 substrates in smokers. Smoking-induced changes in hepatic CYP1A2 abundance were extrapolated from reported in vivo caffeine clearance data for sub-groups of a smoking population that were categorized according to their daily cigarette consumption. These abundance values together with in vitro-in vivo extrapolation (IVIVE) within the Simcyp population-based Simulator were used to predict the clearances of caffeine, theophylline, and clozapine in smokers. The model was used subsequently to predict differences in oral clearance between smoker and non-smoker cohorts in a Phase 1 clinical trial involving PF-2400013, a drug metabolized by CYP1A2. Estimated hepatic CYP1A2 abundance values were 52, 64, 79, 90, and 94pmol/mg microsomal protein for subjects smoking 0, 1-5, 6-10, 11-20, and >20 cigarettes/day respectively. Predicted -fold increases in oral clearance of caffeine, theophylline and clozapine in smokers relative to non-smokers were consistent with observed data. The validated model was able to recover the smoking-induced increase in oral clearance of PF-2400013; predicted and observed mean (CV%) values in male nonsmokers and smokers were 90L/h (40%) and 141L/h (34%) respectively, and 100L/h (58%) and 131L/h (33%) respectively. This study demonstrates that it may be possible to predict the clearance of CYP1A2 substrates in smoking populations using quantitative estimates of CYP1A2 abundance based on daily cigarette consumption in conjunction with an IVIVE approach.