CYP1A2 contributes to the metabolism of mefloquine: Exploration using in vitro metabolism and physiologically-based pharmacokinetic modelling.

Abstract

Mefloquine is an antimalarial drug routinely used for prophylaxis and in the treatment of malaria. Approximately 50% of mefloquine metabolism, both in vitro and in vivo, is mediated by CYP3A4 with the remaining contributions by other CYP450 isoforms unaccounted for. This study aimed to determine the contribution of CYP450s to mefloquine metabolism and incorporate this knowledge into a physiologically-based pharmacokinetic model. The data in human liver microsomes demonstrated the involvement of CYP3A4/5 as well as the previously unreported contribution of CYP1A2 to mefloquine metabolism. The fraction metabolized by CYP1A2 (fm,CYP1A2) was estimated to be at least 50% using chemical inhibitors and pooled human liver microsomes and confirmed using recombinant human CYP450 enzymes. A physiologically-based pharmacokinetic model built in Simcyp using the fm,CYP values recaptured observed clinical pharmacokinetic data-71 % of the simulated area under the curve (AUC) values were within 1.25-fold of the observed clinical data, and all simulated AUC values were within 2-fold of observed data. Simulated mefloquine exposures increased by 88% when an interaction with fluvoxamine, a CYP1A2 inhibitor was modeled. Modeling showed that heavy smoking, and subsequent induction of CYP1A2, had a notable effect on mefloquine exposure. CYP1A2 genotype status also influenced mefloquine exposure with a predicted AUC ratio of 1.68 in a simulated population of CYP1A2 poor metabolizers. The involvement of CYP1A2 in mefloquine metabolism suggests a previously unreported drug-drug interaction risk. Looking forward, the analysis here suggests the clinical exploration of the interaction between mefloquine and CYP1A2. SIGNIFICANCE STATEMENT: Despite the widespread use of mefloquine in malaria prophylaxis and treatment, its metabolism is not completely characterized. This has implications for understanding and predicting drug-drug interactions involving mefloquine. Here, we identify CYP1A2 as a key enzyme involved in mefloquine metabolism and use physiologically-based pharmacokinetic modeling to demonstrate the contribution of this route to interactions with mefloquine. The in vitro data and revised physiologically-based pharmacokinetic model are important starting points for future exploration of this pathway using clinical data.