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Clin Pharmacol Drug Dev. 2019 Jan;8(1):107-118. doi: 10.1002/cpdd.575. Epub 2018 May 25.

Pharmacokinetic Study of Rucaparib in Patients With Advanced Solid Tumors.

Author information

1
Dana-Farber Cancer Institute, Boston, MA, USA.
2
UCL Cancer Institute, London, United Kingdom.
3
Sarah Cannon Research Institute at Tennessee Oncology, Nashville, TN, USA.
4
Yale University, New Haven, CT, USA.
5
Sarah Cannon Research Institute at Florida Cancer Specialists, Sarasota, FL, USA.
6
Northern Centre for Cancer Care, Newcastle upon Tyne, United Kingdom.
7
Clovis Oncology, Inc., Boulder, CO, USA.

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

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