Pharmacokinetic Study of Rucaparib in Patients With Advanced Solid Tumors
Geoffrey I Shapiro, Rebecca S Kristeleit, Howard A Burris, Patricia LoRusso, Manish R Patel, Yvette Drew, Heidi Giordano, Lara Maloney, Simon Watkins, Sandra Goble, Sarah Jaw-Tsai, Jim J Xiao, Geoffrey I Shapiro, Rebecca S Kristeleit, Howard A Burris, Patricia LoRusso, Manish R Patel, Yvette Drew, Heidi Giordano, Lara Maloney, Simon Watkins, Sandra Goble, Sarah Jaw-Tsai, Jim J Xiao
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
References
- Schreiber V, Dantzer F, Ame JC, de Murcia G. Poly(ADP‐ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol. 2006;7(7):517–528.
- Ryu KW, Kim DS, Kraus WL. New facets in the regulation of gene expression by ADP‐ribosylation and poly(ADP‐ribose) polymerases. Chem Rev. 2015;115(6):2453–2481.
- Helleday T, Lo J, van Gent DC, Engelward BP. DNA double‐strand break repair: from mechanistic understanding to cancer treatment. DNA Repair. 2007;6(7):923–935.
- Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA. DNA repair pathways as targets for cancer therapy. Nat Rev Cancer. 2008;8(3):193–204.
- Moynahan ME, Chiu JW, Koller BH, Jasin M. BRCA1 controls homology‐directed DNA repair. Mol Cell. 1999;4(4):511–518.
- Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology‐directed repair of chromosomal breaks. Mol Cell. 2001;7(2):263–272.
- Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108(2):171–182.
- Murai J, Huang SY, Renaud A, et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther. 2014;13(2):433–443.
- Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double‐strand break repair. J Clin Oncol. 2008;26(22):3785–3790.
- Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings. Mol Oncol. 2011;5(4):387–393.
- Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D'Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5(11):1137–1154.
- Wahlberg E, Karlberg T, Kouznetsova E, et al. Family‐wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat Biotechnol. 2012;30(3):283–288.
- Thomas HD, Calabrese CR, Batey MA, et al. Preclinical selection of a novel poly(ADP‐ribose) polymerase inhibitor for clinical trial. Mol Cancer Ther. 2007;6(3):945–956.
- 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.
- Domchek SM, Hendifar AE, McWilliams RR, et al. RUCAPANC: An open‐label, phase 2 trial of the PARP inhibitor rucaparib in patients (pts) with pancreatic cancer (PC) and a known deleterious germline or somatic BRCA mutation. J Clin Oncol. 2016;34(15 suppl):abst 4110.
- Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum‐sensitive high‐grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open‐label, phase 2 trial. Lancet Oncol. 2017;18(1):75–87.
- Xiao JJ, Green M, Ma SC, et al. Population pharmacokinetics (PK) of rucaparib (CO‐338) in patients with advanced ovarian cancer (AOC) or other solid tumors. Clin Pharmacol Ther. 2017;101(S1):S5–S99.
- Smith BP, Vandenhende FR, DeSante KA, et al. Confidence interval criteria for assessment of dose proportionality. Pharm Res. 2000;17(10):1278–1283.
- Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double‐blind, placebo‐controlled, phase 3 trial. Lancet. 2017;390(10106):1949–1961.
- Wilson RH, Evans TJ, Middleton MR, et al. A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours. Br J Cancer. 2017;116(7):884–892.
- Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993;10(7):1093–1095.
Source: PubMed