Drug–Drug Interaction Potential of Darolutamide: In Vitro and Clinical Studies
Eur J Drug Metab Pharmacokinet (2019). https://doi.org/10.1007/s13318-019-00577-5
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Background and Objectives Darolutamide is a novel androgen
receptor (AR) antagonist approved for the treatment of nonmetastatic
castration-resistant prostate cancer (nmCRPC). Accordingly, the drug–drug
interaction (DDI) potential of darolutamide was investigated in both nonclinical and clinical studies.
Methods In vitro studies were performed to determine the potential for
darolutamide to be a substrate, inducer or inhibitor for cytochrome P450 (CYP)
isoforms, other metabolizing enzymes and drug transporters. A phase I
drug-interaction study in healthy volunteers evaluated the impact of
co-administering rifampicin [CYP3A4 and P-glycoprotein (P-gp) inducer] and itraconazole
[CYP3A4, P-gp and breast cancer resistance protein (BCRP) inhibitor] on the
pharmacokinetics of darolutamide.
Two further phase I studies assessed the impact of co-administering oral darolutamide on the pharmacokinetics of midazolam (sensitive CYP3A4 substrate) and dabigatran etexilate (P-gp substrate) and the impact on the pharmacokinetics of co-administered rosuvastatin [a substrate for BCRP, organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and organic anion transporter (OAT)3].
Results In vitro, darolutamide was predominantly metabolized via oxidative
biotransformation catalyzed by CYP3A4 and was identified as a substrate for
P-gp and BCRP. The enzymatic activity of nine CYP isoforms was not inhibited or
slightly inhibited in vitro with darolutamide, and a rank order and mechanistic
static assessment indicated that risk of clinically relevant DDIs via CYP
inhibition is very low. In vitro, darolutamide exhibited no relevant induction
of CYP1A2 or CYP2B6 activity. Inhibition of BCRP-, P-gp-, OAT3-, MATE1-, MATE2-K-, OATP1B1-
and OATP1B3-mediated transport was observed in vitro. Phase I data showed that
darolutamide exposure increased 1.75-fold with co-administered itraconazole and
decreased by 72% with rifampicin. Co-administration of darolutamide with
CYP3A4/P-gp substrates showed no effect or only minor effects. Rosuvastatin
exposure increased 5.2-fold with darolutamide because of BCRP and probably also OATPB1/OATPB3
Conclusions Darolutamide has a low potential for
clinically relevant DDIs with drugs that are substrates for CYP or P-gp; increased
exposure of BCRP and probably OATP substrates was the main interaction of note.