Evaluation of in vitro absorption, distribution, metabolism, and excretion and assessment of drug-drug interaction of rucaparib, an orally potent poly(ADP-ribose) polymerase inhibitor

Abstract

1. The absorption, distribution, metabolism, elimination, and drug-drug interaction (DDI) potential of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib was characterised in vitro.

2. Rucaparib showed moderate cellular permeability, moderate human plasma protein binding (70.2%), and slow metabolism in human liver microsomes (HLMs). In HLMs, cytochrome P450 (CYP) 1A2 and CYP3A contributed to the metabolism of rucaparib to its major metabolite M324 with estimated fractions of metabolism catalysed by CYP (fm,CYP) of 0.27 and 0.64, respectively. Rucaparib reversibly inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3As (IC₅₀, 3.55, 12.9, 5.42, 41.6, and 17.2–22.9 µM [2 substrates], respectively), but not CYP2B6 or CYP2C8 (>190 µM). No time-dependent inhibition of any CYP was observed. In cultured human hepatocytes, rucaparib showed concentration-dependent induction of CYP1A2 mRNA and downregulation of CYP3A4 and CYP2B6 mRNA. In transfected cells expressing drug transporters, rucaparib was a substrate for P-gp and BCRP, but not for OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. Rucaparib inhibited P-gp and BCRP (IC₅₀, 169 and 55 µM, respectively) and slightly inhibited OATP1B1, OATP1B3, OAT1, and OAT3 (66%, 58%, 58%, and 42% inhibition, respectively) at 300 µM. Rucaparib inhibited OCT1, OCT2, MATE1, and MATE2-K (IC₅₀, 4.3, 31, 0.63, and 0.19 μM, respectively).

3. DDI risk assessment using static models suggested potential CYP-related DDIs, with rucaparib as a perpetrator. Caution is advised when co-administering rucaparib with sensitive substrates of MATEs, OCT1, and OCT2.

Keywords:

• PARP inhibitor
• rucaparib
• in vitro ADME characterisation
• drug-drug interactions
• efflux transporters (P-gp
• BCRP
• MATE)
• uptake transporters (OATP
• OAT
• OCT)

Acknowledgements

We would like to thank Cheryl Chun and Peter Morello of Clovis Oncology, Inc., for their assistance and feedback during the development of this manuscript.

Data sharing statement

Requests for the datasets for the results reported in this publication will be made available to qualified researchers following submission of a methodologically sound proposal to [email protected]. Data will be made available for such requests following online publication of this article and for 1 year thereafter in compliance with applicable privacy laws, data protection, and requirements for consent and anonymisation. Data will be provided by Clovis Oncology.

Disclosure statement

Liao, Beltman, Simmons, Harding, and Xiao are employees of Clovis Oncology, Inc., and may own stock/have stock options in that company. Jaw-Tsai was an employee of Clovis Oncology at the time of the study.

Additional information

Funding

This study was supported by Clovis Oncology, Inc. Writing and editorial assistance funded by Clovis Oncology was provided by Nathan Yardley, PhD, Nicole Farra, PhD, and Shannon Davis of Ashfield Healthcare Communications (Middletown, CT).