A phase 1, open-label, drug-drug interaction study of rucaparib with rosuvastatin and oral contraceptives in patients with advanced solid tumors

Mingxiang Liao, Krzysztof G Jeziorski, Monika Tomaszewska-Kiecana, István Láng, Marek Jasiówka, Viera Skarbová, Piotr Centkowski, Rodryg Ramlau, Maria Górnaś, John Lee, Sarah Edwards, Jenn Habeck, Eileen Nash, Nikolay Grechko, Jim J Xiao, Mingxiang Liao, Krzysztof G Jeziorski, Monika Tomaszewska-Kiecana, István Láng, Marek Jasiówka, Viera Skarbová, Piotr Centkowski, Rodryg Ramlau, Maria Górnaś, John Lee, Sarah Edwards, Jenn Habeck, Eileen Nash, Nikolay Grechko, Jim J Xiao

Abstract

Purpose: This 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.

Methods: Patients 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.

Results: Thirty-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.

Conclusion: Rucaparib 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.

Keywords: BCRP; Drug–drug interaction; Oncology; Oral contraceptives; Rucaparib.

Conflict of interest statement

RR has served in a consulting or advisory role for Pfizer, Takeda, Boehringer Ingelheim, Roche, MSD, Novartis, and Bristol-Myers Squibb. EN has served in a consulting or advisory role for Bay Trials Unlimited, LLC. ML, JL, SE, JH, NG, and JX are employees of Clovis Oncology and may own stock or have stock options in that company. KGJ, MT-K, IL, MJ, VS, PC, and MG declare no conflict of interest.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
Arithmetic mean (SD) plasma concentration–time profiles for rosuvastatin (A) and oral contraceptives, ethinylestradiol (B) and levonorgestrel (C), with and without rucaparib (PK analysis population). PK pharmacokinetics, SD standard deviation
Fig. 3
Fig. 3
The effect of rucaparib on the PK of rosuvastatin and oral contraceptives (DDI analysis population). AUC area under the concentration–time curve, AUC0–inf AUC extrapolated from time 0 to infinity, AUC0–last AUC from time 0 up to the last time point with a quantifiable concentration, CI confidence interval, Cmax maximum plasma concentration, DDI drug–drug interaction, GMR geometric mean ratio

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