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

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.

Clinical Pharmacokinetics and Pharmacodynamics of Rucaparib

“…No studies of rucaparib in healthy volunteers have been performed because PARP inhibitors are clastogenic [ 22 , 41 ]. Intensive PK data for rucaparib were obtained from 238 patients after administration of single or multiple doses in the following: a first-in-human phase I study [ 42 ], absolute oral bioavailability study [ 43 ] (A4991014; NCT01009190), ascending dose and food-effect phase I–II studies (Study 10) [ 44 ], mass balance study (NCT02986100) [ 45 ], hepatic impairment study (NCT03521037) [ 46 ], drug interaction studies (NCT02740712, NCT03954366) [ 47 , 48 ], and a phase I dose-escalation study in Japanese patients (RUCA-J; NCT03499444) [ 49 ]. Additionally, sparse PK data were collected from >1027 patients in Study 10 [ 44 ], ARIEL2 Part 1 [ 32 ], ARIEL3, TRITON2, and the phase III TRITON3 study (NCT02975934) of rucaparib in the mCRPC setting.…”

“…The potential for DDIs associated with rucaparib and concomitant medications have been investigated by the use of dedicated in vitro testing and clinical studies in patients with an advanced solid tumor [ 47 , 48 , 54 , 61 ].…”

“…AUC 0 – 72h area under the concentration–time curve from time 0 to 72 h, AUC 0 – 96h AUC from time 0 to 96 h, AUC 0 – inf AUC extrapolated from time 0 to infinity, AUC 0 – last AUC from time 0 up to the last timepoint with a quantifiable concentration, BCRP breast cancer resistance protein, CI c onfidence interval, C max maximum plasma concentration, CYP cytochrome P450, GMR geometric mean ratio, P-gp P-glycoprotein. Adapted from Xiao et al [ 47 ] and Liao et al [ 48 ]. …”

“… Table adapted from Xiao et al [ 47 ] and Liao et al [ 48 ] %CV percent coefficient of variation, AUC area under the concentration–time curve, AUC 0 – 72h AUC from time 0 to 72 h, AUC 0 – 96h AUC from time 0 to 96 h, AUC 0 – inf AUC from time 0 extrapolated to infinity, AUC τ,ss AUC over a dosing interval τ (12 h) at steady state, C max maximum plasma concentration, C max,ss maximum plasma concentration during a dosing interval at steady state, CYP cytochrome P450, DDI drug–drug interaction, NA not applicable, PK , pharmacokinetic, t 1/2 elimination half-life, TEAE treatment-emergent adverse event, t max time to maximum concentration, t max , ss time to maximum concentration at steady state a For t max , data are reported as median (minimum, maximum) b AUC 0–inf is not reported because percent of extrapolated AUC was < 20% for ≤ 1 patient c The t 1/2 is not reported because of uncertainty in the reliability of t 1/2 estimation d n = 17 e n = 16 f n = 11 g n = 12 h AUC 0–inf geometric mean ratio for oral contraceptives were not calculated because ethinylestradiol AUC 0–inf was not accurately determined owing to the high (> 20%) percentage of extrapolation in 7 out of 18 patients when oral contraceptives were dosed alone and 5 out of 17 patients when oral contraceptives were dosed with rucaparib i n = 10 j n = 7 k n = 15 …”

“…In an open-label phase I study (NCT03954366), the effects of rucaparib on the PK of BCRP substrate rosuvastatin and oral contraceptives ethinylestradiol and levonorgestrel were evaluated in patients with solid tumors [ 48 ]. Rucaparib 600 mg BID for 2 weeks weakly increased the plasma exposures of rosuvastatin and the oral contraceptives (Table 2 , Fig.…”