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

Abstract

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 [Cmax], 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 (Cmax, 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 (Cmax, 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 (Cmax, 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.

Conflict of interest statement

Hamim Zahir reports employment with Daiichi Sankyo, Inc. during the time of the study. Jonathan Greenberg reports employment with and stock/stock options in Daiichi Sankyo, Inc. Dale Shuster reports employment, stock/stock options in, and patents with Daiichi Sankyo, Inc. Ching Hsu reports employment and stock/stock options in Daiichi Sankyo, Inc. Kengo Watanabe reports employment with Daiichi Sankyo, Co., Ltd. Frank LaCreta reports employment with and stock/stock options in Daiichi Sankyo, Inc.

© 2022. The Author(s).

Figures

Fig. 1

Study designs: a, esomeprazole study: an open-label randomized, two-treatment, two-period crossover study; b, itraconazole study: a single-sequence, two-treatment, two-period crossover study; c, rifampin study: a single-sequence, two-treatment, two-period crossover study; d, probenecid study: an open-label randomized, two-treatment, two-period crossover study

Fig. 2

Mean (± standard deviation [SD]) plasma pexidartinib concentration–time profiles by treatment: a, esomeprazole study; b, itraconazole study; c, rifampin study; d, probenecid study. Note: Figures on the left are presented on a natural scale; figures on the right are presented on a logarithmic scale

Fig. 2

Mean (± standard deviation [SD]) plasma pexidartinib concentration–time profiles by treatment: a, esomeprazole study; b, itraconazole study; c, rifampin study; d, probenecid study. Note: Figures on the left are presented on a natural scale; figures on the right are presented on a logarithmic scale

Fig. 3

Mean (± standard deviation [SD]) plasma ZAAD-1006a concentration–time profiles by treatment: a, esomeprazole study, b, itraconazole study, c, rifampin study, d, probenecid study

Fig. 3

Mean (± standard deviation [SD]) plasma ZAAD-1006a concentration–time profiles by treatment: a, esomeprazole study, b, itraconazole study, c, rifampin study, d, probenecid study

Fig. 4

Forest plot (odds ratio) of the effect of a pH modifier (esomeprazole): a strong cytochrome P450 (CYP) 3A inhibitor (itraconazole) and strong CYP3A inducer (rifampin), and a 5′-diphospho-glucuronosyltransferase inhibitor (probenecid) and the simulated effects of a moderate CYP3A inhibitor (fluconazole) and a moderate CYP3A inducer (efavirenz) on the single dose: a, maximum plasma concentration (Cmax); and b, area under the drug plasma concentration–time curve from time 0 to infinity (AUC∞) of pexidartinib presented as 90% confidence intervals

Fig. 5

Simulated mean plasma concentration–time profiles of pexidartinib: a, multiple oral doses of pexidartinib (400 mg twice daily) in the absence of (solid black line) and presence (dashed black line) of fluconazole 200 mg once daily (400 mg on day 1) in subjects with cancer using the original model; b, single oral dose of pexidartinib (400 mg) in the absence of (solid black line) efavirenz and on the eighth day of 20 days of dosing of efavirenz (dashed black line) 600 mg daily in subjects with cancer using the final model