Effect of enzalutamide on PK of P‐gp and BCRP substrates in cancer patients: CYP450 induction may not always predict overall effect on transporters

Abstract

Drug-drug interaction (DDI) is an important consideration for clinical decision making in prostate cancer treatment. The objective of this study was to evaluate the effect of enzalutamide, an oral androgen receptor inhibitor, on the pharmacokinetics (PK) of digoxin (P-glycoprotein [P-gp] probe substrate) and rosuvastatin (breast cancer resistance protein [BCRP] probe substrate) in men with metastatic castration-resistant prostate cancer (mCRPC). This was a phase I, open-label, fixed-sequence, crossover study (NCT04094519). Eligible men with mCRPC received a single dose of transporter probe cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin plus enzalutamide placebo-to-match on day 1. On day 8, patients started 160 mg enzalutamide once daily through day 71. On day 64, patients also received a single dose of the cocktail. The primary end points were digoxin and rosuvastatin plasma maximum concentration (C max ), area under the concentration-time curve from the time of dosing to the last measurable concentration (AUC last ), and AUC from the time of dosing extrapolated to time infinity (AUC inf ). Secondary end points were enzalutamide and N-desmethyl enzalutamide (metabolite) plasma C max , AUC during a dosing interval, where tau is the length of the dosing interval (AUC tau ), and concentration immediately prior to dosing at multiple dosing (C trough ). When administered with enzalutamide, there was a 17% increase in C max , 29% increase in AUC last , and 33% increase in AUC inf of plasma digoxin compared to digoxin alone, indicating that enzalutamide is a "mild" inhibitor of P-gp. No PK interaction was observed between enzalutamide and rosuvastatin (BCRP probe substrate). The PK of enzalutamide and N-desmethyl enzalutamide were in agreement with previously reported data.The potential for transporter-mediated DDI between enzalutamide and digoxin and rosuvastatin is low in men with prostate cancer. Therefore, concomitant How to cite this article: Poondru S, Ghicavii V, Khosravan R, et al. Effect of enzalutamide on PK of P-gp and BCRP substrates in cancer patients: CYP450 induction may not always predict overall effect on transporters.

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

“…As enzalutamide showed both P-gp inhibition and induction effects in in vitro studies, a clinical DDI study would only reveal the net effect on P-gp. The clinical net effect of enzalutamide on P-gp was investigated with a typical P-gp substrate, digoxin [ 3 ]. Multiple oral administration of 160 mg of enzalutamide increased digoxin AUC and C max by 29% and 17%, respectively, indicating enzalutamide’s inhibition effect on P-gp outweighed its induction effect.…”

“…Under these assumptions, C max ratio was slightly overpredicted which may be a representation of stronger induction or weaker inhibition of intestinal P-gp in the clinical setting compared to model assumptions. In the clinical study, a decrease in renal clearance of digoxin was observed in the presence of enzalutamide, which may be a result of enzalutamide’s inhibitory effect on renal P-gp, which is not accounted for in the present PBPK analysis [ 3 ]. Since inhibition of renal P-gp results in an increase in AUC only, not incorporating this mechanism into the model could be a possible reason for overestimation in the C max ratio.…”

“…The ability of the enzalutamide and M2 PBPK models to predict CYP3A induction was confirmed using a DDI simulation with midazolam as the victim. The net effect of enzalutamide on P-gp was investigated in a clinical DDI study using digoxin as a typical P-gp substrate [ 3 ]. Enzalutamide inhibition and induction effects to P-gp were optimized based on the results from a clinical DDI study.…”

“…Enzalutamide did not cause clinically meaningful changes in exposure to the CYP1A2, CYP2C8, or CYP2D6 substrates. In a clinical DDI study, enzalutamide increased the AUC of digoxin, a typical P-gp substrate, by 29%, indicating the net effect of enzalutamide on P-gp is inhibition-based [ 3 ]. Clinical DDI study results with rosuvastatin, a typical BCRP substrate, showed that enzalutamide did not change the plasma exposure of rosuvastatin.…”

Enzalutamide: Understanding and Managing Drug Interactions to Improve Patient Safety and Drug Efficacy

“…In vitro DDI studies have indicated that enzalutamide is an inhibitor of P-gp and BCRP [ 34 ], and it has been suggested to have the potential for transporter-mediated DDIs via interactions with P-gp and BCRP when coadministered to patients with medications that are substrates of these efflux transporters [ 35 ]. In addition, enzalutamide could potentially induce P-gp and BCRP as it is a strong inducer of CYP3A4 and because both transporters and CYP3A4 are induced by PXR [ 22 , 24 , 36 ].…”