Evaluation of Absorption and Metabolism-Based DDI Potential of Pexidartinib in Healthy Subjects

BACKGROUND AND OBJECTIVE: Pexidartinib is a novel oral small-molecule inhibitor that selectively targets colony-stimulating factor 1 receptor, KIT proto-oncogene receptor tyrosine kinase, and FMS-like tyrosine kinase 3 harboring an internal tandem duplication mutation. It is approved in the United States for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Pexidartinib in vitro data indicate the potential for absorption- and metabolism-related drug–drug interactions (DDIs). The objective was to present a comprehensive DDI risk assessment of agents that can impact pexidartinib exposure by altering its absorption and metabolism potentially affecting efficacy and safety of pexidartinib. METHODS: Four open-label crossover studies were performed to assess the effects of a pH modifier (esomeprazole), a strong cytochrome P450 (CYP) 3A4 inhibitor (itraconazole), a strong CYP3A/5′-diphospho-glucuronosyltransferase (UGT) inducer (rifampin), and a UGT inhibitor (probenecid) on the single-dose pharmacokinetics of pexidartinib. In addition, a physiologically based pharmacokinetic model was developed to predict the effect of a moderate CYP3A4 inhibitor (fluconazole) and a moderate CYP3A inducer (efavirenz) on the pharmacokinetics of pexidartinib. RESULTS: Co-administration of pexidartinib with esomeprazole modestly decreased pexidartinib exposure (maximum plasma concentration [C(max)], ng/mL: geometric mean ratio [90% confidence interval (CI)], 45.4% [36.8–55.9]; area under the drug plasma concentration–time curve from time 0 to infinity [AUC(∞)], ng•h/mL: geometric mean ratio [90% CI], 53.1% [47.4–59.3]), likely related to decreased solubility of pexidartinib at increased pH levels. As expected, the strong CYP3A4 inhibitor itraconazole increased pexidartinib exposure (C(max), ng/mL: geometric mean ratio [90% CI], 148.3% [127.8–172.0]; AUC(∞), ng•h/mL: geometric mean ratio [90% CI], 173.0% [160.7–186.3]) while the strong CYP3A/UGT inducer rifampin decreased exposure (C(max), ng/mL: geometric mean ratio [90% CI], 67.1% [53.1–84.8]; AUC(∞), ng•h/mL: geometric mean ratio [90% CI], 37.0% [30.6–44.8]). In addition, UGT inhibition increased pexidartinib exposure (C(max), ng/mL: geometric mean ratio [90% CI], 105.8% [92.4–121.0]; AUC(∞), ng•h/mL: geometric mean ratio [90% CI], 159.8% [143.4–178.0]), consistent with the fact that pexidartinib is a substrate of the UGT1A4 enzyme, which is responsible for the generation of the major metabolite, ZAAD-1006a. CONCLUSIONS: The physiologically based pharmacokinetic model predicted that a moderate CYP3A4 inhibitor and a moderate CYP3A inducer would produce modest increases and decreases, respectively, in pexidartinib exposure. These results provide a basis for pexidartinib dosing recommendations when administered concomitantly with drugs with drug–drug interaction potential, including dose adjustments when concomitant administration cannot be avoided. CLINICAL TRIAL REGISTRATION: Probenecid: phase I trial, NCT03138759, 3 May, 2017; esomeprazole, itraconazole, rifampin: phase I trials, not registered with ClinicalTrials.gov. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-022-01172-9.