Varenicline PBPK Modeling Links Exposure Variability to Renal Transport and Absorption
A model fitted to four clinical datasets and 20 individual profiles suggests that OCT2-mediated renal clearance explains much of varenicline exposure variability, with intestinal absorption also contributing in three individuals.
Separating Clearance from Absorption
Researchers at the University of Southern California and the University of Nevada, Las Vegas used physiologically based pharmacokinetic (PBPK) modeling to examine why varenicline concentrations vary between people. The smoking-cessation drug can cause nausea and vomiting at higher exposure, motivating a mechanistic assessment of renal transport and intestinal absorption.
A population-average model incorporated absorption, metabolism and renal clearance using data from four clinical studies. Its peak-concentration and area-under-the-curve predictions had fold errors of 0.88–1.14. The model included OCT2-mediated renal clearance and lower duodenal and jejunal absorption parameters.
What the Individual Fits Suggested
The team then fitted profiles for 20 individuals by adjusting physiology and OCT2 transport kinetics. Variation in OCT2 capacity accounted for most differences in total exposure. The fitted maximum transport rate ranged from 0.004 to 0.035 mg/s/mg-trans, compared with 0.017 mg/s/mg-trans in the average model. Three of the 20 individuals also required increased jejunal absorption to reproduce their higher peak concentrations.
The authors propose two genetic explanations for further investigation: variation in SLC22A2, which encodes OCT2, could affect renal elimination, while SLCO3A1 variation could alter intestinal pH and the neutral fraction of varenicline.