Physiologically-based pharmacokinetic modeling to predict drug-drug interaction of enzalutamide with combined P-gp and CYP3A substrates

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 C_max for apixaban and a 45% decrease in AUC and a 25% decrease in C_max 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.

Keywords: Apixaban; Drug-drug interaction (DDI); Enzalutamide; P-glycoprotein (P-gp); Physiologically-based pharmacokinetics (PBPK); Rivaroxaban.

Fig. 1

Observed and simulated plasma concentration–time profiles of enzalutamide and M2: (A, B) enzalutamide data after single 160 mg dose in linear and semi-log scales; (C, D) M2 data after single 160 mg dose in linear and semi-log scales; (E, F) enzalutamide data after multiple 160 mg doses in full-time scale and extracting 1176 to 1200 h; (G, H) M2 data after multiple 160 mg doses in full-time scale and extracting 1176 to 1200 h. The data shown are simulated mean (solid line), simulated 5th and 95th percentiles (dashed lines), observed mean (filled circles), and observed individual (open circles)

Fig. 2

Observed and simulated plasma concentration–time profiles of enzalutamide after (A) single and (B) multiple doses at several dose levels. The data shown are simulated mean (lines) and observed mean (markers)

Fig. 3

Observed and simulated plasma concentration–time profiles of digoxin in (A) absence and (B) presence of enzalutamide. The data shown are simulated mean (solid line), simulated 5th and 95th percentiles (dashed lines), observed mean (filled circles), and observed individual (open circles)