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Population pharmacokinetics of rucaparib in patients with advanced ovarian cancer or other solid tumors

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Abstract

Purpose

To develop a population pharmacokinetics (PPK) model for rucaparib, an oral poly(ADP-ribose) polymerase inhibitor.

Methods

The PPK analysis used PK data from patients in Study 1014 (NCT01009190, n = 35), Study 10 (NCT01482715, n = 123), and ARIEL2 (NCT01891344, n = 300), including intensive intravenous data (12–40 mg), intensive and sparse oral data (12–360 mg single-dose, 40–500 mg once daily, and 240–840 mg twice daily [BID]), and intensive single-dose oral data under fasted conditions and after a high-fat meal (40, 300, and 600 mg).

Results

Rucaparib PK was well described by a two-compartment model with sequential zero-order release and first-order absorption and first-order elimination. A high-fat meal slightly increased bioavailability at 600 mg but not at lower doses; this is not considered clinically significant, and rucaparib can be taken with or without food. Covariate effects of baseline creatinine clearance and albumin on rucaparib clearance were identified. Despite numerical increases in exposure with renal impairment, no dose adjustment is recommended for patients with mild or moderate renal impairment. No statistically significant relationships were detected for demographics, hepatic function (normal versus mild impairment), CYP1A2 and CYP2D6 phenotypes, or strong CYP1A2 or CYP2D6 inhibitors. Concomitant proton pump inhibitors showed no clinically significant effect on absorption. External validation of the model with data from ARIEL3 (NCT01968213) and TRITON2 (NCT02952534) studies showed no clinically meaningful PK differences across indications or sex.

Conclusion

The PPK model adequately described rucaparib PK, and none of the covariates evaluated had a clinically relevant effect.

ClinicalTrials.gov

Study 1014 (NCT01009190), Study 10 (NCT01482715), ARIEL2 (NCT01891344), ARIEL3 (NCT01968213), and TRITON2 (NCT02952534).

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Acknowledgements

Medical writing and editorial support funded by Clovis Oncology, Inc., were provided by Nathan Yardley and Stephen Bublitz of Ashfield MedComms, an Ashfield Health company.

Funding

The current analyses were funded by Clovis Oncology, Inc., and were designed in collaboration with the sponsor.

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Authors and Affiliations

  1. Certara Strategic Consulting, Menlo Park, CA, USA

    Michelle L. Green & Shu Chin Ma

  2. Clovis Oncology, Inc., 5500 Flatiron Pkwy, Boulder, CO, 80301, USA

    Sandra Goble, Heidi Giordano, Lara Maloney, Andrew D. Simmons, Jeri Beltman, Thomas C. Harding & Jim J. Xiao

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  1. Michelle L. Green
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Contributions

MLG and JJX designed the population PK analyses. MLG and SCM conducted the analyses. All authors contributed to data analysis and interpretation. SG, HG, LM, ADS, JB, and TCH were involved in the design of the clinical studies. All authors contributed to drafting and critical revision of the manuscript for important intellectual content, approved the final submission draft, and take responsibility for the integrity of the data.

Corresponding author

Correspondence to Jim J. Xiao.

Ethics declarations

Conflict of interest

MLG and SCM were employees of Certara and were paid contractors to Clovis Oncology in connection with the analysis and development of this manuscript. SG, HG, LM, ADS, JB, TCH, and JJX are employees of Clovis Oncology and may own stock or have stock options in that company.

Consent for publication

All authors gave consent for publication.

Ethics approval and consent to participate

For the studies that are included in this analysis, the institutional review board or ethics committee at each site approved the study protocols and patients provided written informed consent per the Declaration of Helsinki and Good Clinical Practice.

Availability of data and material

Requests for deidentified datasets for the results reported in this publication will be made available to qualified researchers following submission of a methodologically sound proposal to medinfo@clovisoncology.com. 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 anonymization. Data will be provided by Clovis Oncology. Clovis Oncology does not share identified participant data or a data dictionary.

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Date of registration: Study 1014 (November 6, 2009), Study 10 (November 30, 2011), ARIEL2 (July 3, 2013), ARIEL3 (October 23, 2013), and TRITON2 (November 2, 2016).

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Green, M.L., Ma, S.C., Goble, S. et al. Population pharmacokinetics of rucaparib in patients with advanced ovarian cancer or other solid tumors. Cancer Chemother Pharmacol 89, 671–682 (2022). https://doi.org/10.1007/s00280-022-04413-7

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  • DOI: https://doi.org/10.1007/s00280-022-04413-7

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