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- Title
Physiologically-based pharmacokinetic modeling to predict drug-drug interaction of enzalutamide with combined P-gp and CYP3A substrates.
- Authors
Otsuka, Yukio; Poondru, Srinivasu; Bonate, Peter L.; Rose, Rachel H.; Jamei, Masoud; Ushigome, Fumihiko; Minematsu, Tsuyoshi
- Abstract
Enzalutamide is known to strongly induce cytochrome P450 3A4 (CYP3A4). Furthermore, enzalutamide showed induction and inhibition of P-glycoprotein (P-gp) in in vitro studies. A clinical drug-drug interaction (DDI) study between enzalutamide and digoxin, a typical P-gp substrate, suggested enzalutamide has weak inhibitory effect on P-gp substrates. Direct oral anticoagulants (DOACs), such as apixaban and rivaroxaban, are dual substrates of CYP3A4 and P-gp, and hence it is recommended to avoid co-administration of these DOACs with combined P-gp and strong CYP3A inducers. Enzalutamide's net effect on P-gp and CYP3A for apixaban and rivaroxaban plasma exposures is of interest to physicians who treat patients for venous thromboembolism with prostate cancer. Accordingly, a physiologically-based pharmacokinetic (PBPK) analysis was performed to predict the magnitude of DDI on apixaban and rivaroxaban exposures in the presence of 160 mg once-daily dosing of enzalutamide. The PBPK models of enzalutamide and M2, a major metabolite of enzalutamide which also has potential to induce CYP3A and P-gp and inhibit P-gp, were developed and verified as perpetrators of CYP3A-and P-gp-mediated interaction. Simulation results predicted a 31% decrease in AUC and no change in Cmax for apixaban and a 45% decrease in AUC and a 25% decrease in Cmax for rivaroxaban when 160 mg multiple doses of enzalutamide were co-administered. In summary, enzalutamide is considered to decrease apixaban and rivaroxaban exposure through the combined effects of CYP3A induction and net P-gp inhibition. Concurrent use of these drugs warrants careful monitoring for efficacy and safety.
- Subjects
DRUG interactions; APIXABAN; CYTOCHROME P-450 CYP3A; ORAL medication; PHARMACOKINETICS; THROMBOEMBOLISM
- Publication
Journal of Pharmacokinetics & Pharmacodynamics, 2023, Vol 50, Issue 5, p365
- ISSN
1567-567X
- Publication type
Article
- DOI
10.1007/s10928-023-09867-7