ABCB1, ABCG2, and CES1 are Key Determinants of the Pharmacokinetics of KRASG12C Inhibitor Divarasib

Divarasib is a selective KRASG12C inhibitor currently in phase 3 trials for treatment of NSCLC. Drug transporters and metabolic enzymes can markedly influence oral drug disposition. We therefore examined whether the efflux transporters ABCB1 and ABCG2, the influx transporter OATP1, and the enzymes CYP3A and CES1 affect the plasma and tissue distribution of divarasib. Using genetically modified cell lines and mouse models, we assessed transporter- and enzyme-mediated effects on divarasib pharmacokinetics. Transepithelial transport assays, oral pharmacokinetic studies, and ex vivo esterase assays were performed to evaluate divarasib transport, plasma exposure, tissue distribution, metabolism, and protein binding. Divarasib was efficiently transported by hABCB1, mAbcb1a, hABCG2 and mAbcg2 in vitro. Abcb1a/b−/− and Abcb1a/b;Abcg2−/− mice displayed a >4-fold increase in plasma exposure and 7.1- to 16-fold higher brain-to-plasma ratios compared to wild-type mice. Small intestinal content-to-plasma ratios were significantly reduced in Abcb1a/b−/− and Abcb1a/b;Abcg2−/− mice. Coadministration of the dual ABCB1/ABCG2 inhibitor elacridar in wild-type mice increased divarasib plasma exposure to the level seen in Abcb1a/b;Abcg2−/− mice, but only modestly enhanced brain penetration. Oatp1a/b deficiency did not alter divarasib pharmacokinetics, and neither mCyp3a nor hCYP3A4 affected its oral availability. Ces1 ablation strongly decreased divarasib plasma exposure, suggesting binding to plasma Ces1c. Accordingly, divarasib inhibited plasma Ces1c-mediated hydrolysis of 4-nitrophenyl acetate. Increased tissue concentrations in Ces1−/− mice further suggested decreased hydrolysis of divarasib by (non-Ces1c) Ces1 enzymes, or compensatory downregulation of other divarasib clearance process(es). The obtained pharmacokinetic insights may support optimization of divarasib clinical application, efficacy and safety, and highlight potential drug−drug interaction risks.