PBPK Modeling of Varenicline: Relating Variable Pharmacokinetics to Genomics.

Abstract

Background and objective: Varenicline is a smoking cessation drug that requires dosing over days to weeks to reach a pharmacologically effective concentration, since higher doses may result in nausea and vomiting. High interindividual variability in varenicline pharmacokinetics may also be related to these adverse effects. This study aimed to identify possible genetic causes of this variability using physiologically based pharmacokinetic (PBPK) modeling.

Methods: A mean PBPK model of varenicline with mechanistic absorption, metabolism, and renal clearance was built using four patient populations. This model was then used to simulate pharmacokinetics in 20 individuals, adjusting SLC22A2 (OCT2) transporter kinetics and physiology to fit the simulations to the observed data.

Results: The mean model included parameters for renal clearance through OCT2 (V_max 0.017 mg/s/mg-trans) and reduced duodenal and jejunal absorption. This model aligned with observed data from four studies (C_max and AUC fold errors 0.88-1.14). In the individual models, AUC differences were mainly accounted for by OCT2 kinetics [V_max 0.004 (4.3 × decrease from the mean) to 0.035 (2.1 × increase) mg/s/mg-trans)], but 3/20 subjects (15%) with a high C_max also required increased jejunal absorption.

Conclusion: Individuals with high varenicline exposure may have reduced renal elimination due to genetic variation in SLC22A2 (OCT2), while those with higher C_max may have elevated intestinal pH, giving a higher level of neutral varenicline. The effect on pH may be due to genetic variation in SLCO3A1, a bile acid transporter related to nausea after varenicline dosing.