Pharmacokinetic population modeling of nicotine incorporating CYP2A6 genotypes following different routes of administration

Abstract

Purpose We developed a comprehensive population pharmacokinetic (PK) model to quantify the influence of CYP2A6 genetic polymorphisms (GP) and covariates (COV) on the PK of nicotine following different routes of administration, and to predict individual subjects' PK. Methods Two groups of 64 and 278 subjects received oral (OR) and IV administration of deuterium-labeled nicotine. Genotyping of CYP2A6 (*1A, *1B, *1x2, *2, *4, *7, and *9) was carried out. CYP2A6 GP is incorporated using indicator variables (Gi): if a subject carries the i-th genotype Gi is 1, and it is 0 otherwise. The influence of CYP2A6 GP on clearance, e.g., is expressed as: CL= Σmi=1 θιGi, where m is the number of different genotypes. The analysis yields GP and COV influence on CL, Q, V1, V2 (IV) and ka, CL/F, Q, V1/F ((OR). Results Body weight and age were significant COV for both IV and OR administrations. Smoking, marital status, education, BMI were not significant. The Asian group showed a significant decrease in clearance (52.8%) compared to other racial groups. Race was not significant after incorporating CYP2A6 GP. CYP2A6 *4/*4 decreased the clearance to 31.5 % of the wild-type clearance. Conclusions We elucidated the relationships between CYP2A6 GP and COV and nicotine clearance. We are developing the model to incorporate patch administration (PA) and developing a Bayesian model for OR and PA. Clinical Pharmacology & Therapeutics (2005) 77, P21–P21; doi: 10.1016/j.clpt.2004.11.080