SUMMARY

• No drug interaction studies have been performed with AKEEGA. Interactions that have been identified in studies with niraparib or abiraterone acetate as single agents determine the interactions that may occur with AKEEGA.¹
• Niraparib is primarily metabolized by carboxylesterases (CEs) to inactive metabolite and subsequently converted to glucuronide by UDP-glucuronosyltransferases (UGTs).¹ Following oral administration, abiraterone acetate is hydrolyzed to the active metabolite, abiraterone, likely through esterase activity.²
• Inhibition (CYPs, UGTs, and transporters)¹:
  • Niraparib is not an inhibitor of CYP1A1/2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, UGT isoforms, BSEP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. Niraparib inhibits BCRP, MATE1, and MATE2-K transporters. The potential of niraparib to inhibit CYP3A4 at intestinal levels has not been established, and caution is recommended when AKEEGA is combined with active substances, the metabolism of which are CYP3A4-dependent; and those which have a narrow therapeutic range.
  • Abiraterone acetate is an inhibitor of CYP2D6 and CYP2C8.³ Caution is advised when AKEEGA is combined with medicinal products activated by or metabolized by CYP2D6, particularly with a narrow therapeutic index. Dose reduction of medicinal products with a narrow therapeutic index that are metabolized by CYP2D6 should be considered. Patients should be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with AKEEGA. In vitro, abiraterone is an inhibitor of OATP1B1, and may increase concentrations of drugs that are eliminated by OATP1B1. No clinical data are available to confirm transporter-based interactions for abiraterone.
• Induction of CYPs¹:
  • Niraparib is not an inducer of CYP3A4. Based on in vitro data, niraparib weakly induces CYP1A2 at high concentrations. Caution is recommended when AKEEGA is combined with CYP1A2 substrates with a narrow therapeutic index.
• As a substrate of CYPs and transporters¹:
  • CYP mediated oxidative metabolism of niraparib is minimal in vivo. Niraparib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
  • Abiraterone is a substrate of CYP3A4 in vitro. Strong inducers of CYP3A4 during treatment with AKEEGA are to be avoided unless there is no therapeutic alternative. There are no clinical data available to confirm transporter-based interaction.
• A phase 1b study (BEDIVERE) evaluated the safety and pharmacokinetics (PK) of niraparib in combination with androgen-targeted therapy (apalutamide or abiraterone acetate plus prednisone [AAP]) in men with metastatic-castration resistant prostate cancer (mCRPC).⁴
  • Coadministration of niraparib 200 mg and abiraterone acetate 1000 mg had no significant effect on the PK of either niraparib or abiraterone acetate.
  • Coadministration of niraparib 200 mg and the androgen-receptor (AR) inhibitor apalutamide 240 mg resulted in reduced exposures of niraparib.

drug interactions

For up-to-date drug interaction, pharmacokinetic, and pharmacodynamic clinical data pertaining to specific medicinal agents, please review the local labeling of AKEEGA and/or contact the manufacturers of these agents for additional information.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) conducted on 04 June 2024 did not identify any relevant citations pertaining to this topic in patients with prostate cancer.