Pharmacokinetic Study of Rucaparib in Patients With Advanced Solid Tumors

Abstract

The phase 1-2 study CO-338-010 (Study 10; NCT01482715) is evaluating single-agent rucaparib, a poly(ADP-ribose) polymerase inhibitor, administered orally to patients with an advanced solid tumor. In the dose escalation phase (Part 1), we characterized the single-dose and steady-state pharmacokinetic profiles of rucaparib administered once daily (QD; dose range, 40-500 mg; n = 16) or twice daily (BID; dose range, 240-840 mg; n = 30). Across all dosing schedules examined, the plasma exposure of rucaparib was approximately dose proportional; half-life was approximately 17 hours, and median time to maximum concentration (tmax ) ranged from 1.5 to 6.0 hours after a single dose and 1.5 to 4.0 hours following repeated dosing. The steady-state accumulation ratio ranged from 1.60 to 2.33 following QD dosing and 1.47 to 5.44 following BID dosing. No effect of food on rucaparib pharmacokinetics was observed with a single dose of 40 mg (n = 3) or 300 mg (n = 6). In a phase 2 portion of the study (Part 3), the pharmacokinetic profile of rucaparib was further evaluated at the recommended phase 2 dose of 600 mg BID (n = 26). The mean (coefficient of variation) steady-state maximum concentration (Cmax ) and area under the concentration-time curve from time zero to 12 hours (AUC0-12h ) were 1940 ng/mL (54%) and 16 900 ng ⋅ h/mL (54%), respectively. A high-fat meal moderately increased rucaparib exposure. The fed-to-fasted geometric mean ratios (90% confidence interval [CI]) for AUC0-24h and Cmax were 138% (117%-162%) and 120% (99.1%-146%); the median (90%CI) tmax delay was 2.5 (0.5-4.4) hours.

Keywords: PARP inhibition; food effect; pharmacokinetics; rucaparib; tablet.

© 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Figures

Figure 1

Patient flow diagram. BID, twice daily; PK, pharmacokinetics; QD, once daily.

Figure 2

Rucaparib plasma concentration‐time profiles following once daily (QD [A, B]) and twice daily (BID [C, D]) oral administration. Error bars represent standard deviation (SD). Adapted from Kristeleit R, Shapiro GI, Burris HA, et al. A phase I‐II study of the oral poly(ADP‐ribose) polymerase inhibitor rucaparib in patients with germline BRCA1/2‐mutated ovarian carcinoma or other solid tumors. Clin Cancer Res. 2017;23(15):4095‐4106 [Supplementary Appendix, Figures S1 and S2].14

Figure 3

Mean (standard error [SE]) rucaparib plasma trough concentrations vs time by cohort (QD [A] and BID [B] dosing schedules). Note: Preliminary food effect test cohorts were excluded. BID, twice daily; QD, once daily.

Figure 4

Observed and predicted relationship between rucaparib dose and exposure at steady state on once daily (QD [A, B]) and twice daily (BID [C, D]) dosing schedules. Open circles represent observed individual steady‐state Cmax or AUC0‐t, solid lines represent model prediction, and shaded areas represent 90% confidence intervals (CIs). AUC0‐t, area under the concentration‐time curve from time 0 to last measurable concentration (t = 24 hours for QD dosing schedule; t = 12 hours for BID dosing schedule); AUC0‐12h, area under the concentration‐time curve from 0 to 12 hours; AUC0‐24h, area under the concentration‐time curve from 0 to 24 hours; Cmax, maximum plasma concentration. Adapted from Kristeleit R, Shapiro GI, Burris HA, et al. A phase I‐II study of the oral poly(ADP‐ribose) polymerase inhibitor rucaparib in patients with germline BRCA1/2‐mutated ovarian carcinoma or other solid tumors. Clin Cancer Res. 2017;23(15):4095‐4106 [Supplementary Appendix, Figure S3].14

Figure 5

Mean (standard deviation [SD]) rucaparib plasma concentration‐time profiles under fasted conditions and with a high‐fat meal following a single dose of rucaparib at 40 and 300 mg (Part 1) and 600 mg (Part 3) (A), and steady‐state pharmacokinetic profiles following rucaparib 40 and 300 mg QD and 600 mg BID with or without food (B). Food effect was evaluated on cycle 1 days –7 and 1. Steady‐state pharmacokinetics was evaluated on cycle 1 day 15. BID, twice a day; QD, once daily.