Abstract

PurposeThis study aimed at evaluating the effect of rucaparib on the pharmacokinetics of rosuvastatin and oral contraceptives in patients with advanced solid tumors and the safety of rucaparib with and without coadministration of rosuvastatin or oral contraceptives.MethodsPatients received single doses of oral rosuvastatin 20 mg (Arm A) or oral contraceptives ethinylestradiol 30 µg + levonorgestrel 150 µg (Arm B) on days 1 and 19 and continuous doses of rucaparib 600 mg BID from day 5 to 23. Serial blood samples were collected with and without rucaparib for pharmacokinetic analysis.ResultsThirty-six patients (n = 18 each arm) were enrolled and received at least 1 dose of study drug. In the drug–drug interaction analysis (n = 15 each arm), the geometric mean ratio (GMR) of maximum concentration (Cmax) with and without rucaparib was 1.29 for rosuvastatin, 1.09 for ethinylestradiol, and 1.19 for levonorgestrel. GMR of area under the concentration–time curve from time zero to last quantifiable measurement (AUC0–last) was 1.34 for rosuvastatin, 1.43 for ethinylestradiol, and 1.56 for levonorgestrel. There was no increase in frequency of treatment-emergent adverse events (TEAEs) when rucaparib was given with either of the probe drugs. In both arms, most TEAEs were mild in severity and considered unrelated to study treatment.ConclusionRucaparib 600 mg BID weakly increased the plasma exposure to rosuvastatin or oral contraceptives. Rucaparib safety profile when coadministered with rosuvastatin or oral contraceptives was consistent with that of rucaparib monotherapy. Dose adjustments of rosuvastatin and oral contraceptives are not necessary when coadministered with rucaparib.ClinicalTrials.gov NCT03954366; Date of registration May 17, 2019.

Highlights

  • IntroductionOral, small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1, PARP2, and PARP3 [1]

  • Rucaparib is a potent, oral, small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1, PARP2, and PARP3 [1]

  • Rucaparib weakly inhibited CYP3A [9]. These results suggest that steady-state rucaparib is likely to have a limited impact on the exposure of CYP3A substrates and would not reduce the clinical efficacy of oral contraceptives, which are often CYP3A substrates [10, 11]

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Summary

Introduction

Oral, small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1, PARP2, and PARP3 [1]. Rucaparib is approved in the United States and the European Union as monotherapy for the maintenance treatment or treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer [3, 4]. Rucaparib received accelerated approval from the US Food and Drug Administration as mono‐ therapy for adult patients with a deleterious BRCA1 or BRCA2 mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer [3]. The pharmacokinetic (PK) profile of rucaparib as a monotherapy was previously examined in patients from Study 10 (NCT01482715) [4, 5]. Among patients with advanced solid tumors, across all dosages (40–500 mg once daily [QD] or 240–840 mg twice daily [BID]), steady state of plasma

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