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Clinical Trial
. 2021 Aug;88(2):259-270.
doi: 10.1007/s00280-021-04278-2. Epub 2021 Apr 28.

Pharmacokinetics and safety of rucaparib in patients with advanced solid tumors and hepatic impairment

Nikolay Grechko  1 , Viera Skarbova  2 , Monika Tomaszewska-Kiecana  3 , Rodryg Ramlau  4 , Piotr Centkowski  5 , Yvette Drew  6 , Rafal Dziadziuszko  7 , Milada Zemanova  8 , Jeri Beltman  9 , Eileen Nash  10 , Jenn Habeck  11 , Mingxiang Liao  12 , Jim Xiao  13
Affiliations
Clinical Trial

Pharmacokinetics and safety of rucaparib in patients with advanced solid tumors and hepatic impairment

Nikolay Grechko et al. Cancer Chemother Pharmacol. 2021 Aug.

Abstract

Purpose: The poly(ADP-ribose) polymerase inhibitor rucaparib is approved for the treatment of patients with recurrent ovarian and metastatic castration-resistant prostate cancer; however, limited data are available on its use in patients with hepatic dysfunction. This study investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of rucaparib in patients with advanced solid tumors.

Methods: Patients with normal hepatic function or moderate hepatic impairment according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria were enrolled and received a single oral dose of rucaparib 600 mg. Concentrations of rucaparib and its metabolite M324 in plasma and urine were measured. Pharmacokinetic parameters were compared between hepatic function groups, and safety and tolerability were assessed.

Results: Sixteen patients were enrolled (n = 8 per group). Rucaparib maximum concentration (Cmax) was similar, while the area under the concentration-time curve from time 0 to infinity (AUC0-inf) was mildly higher in the moderate hepatic impairment group than in the normal control group (geometric mean ratio, 1.446 [90% CI 0.668-3.131]); similar trends were observed for M324. Eight (50%) patients experienced ≥ 1 treatment-emergent adverse event (TEAE); 2 had normal hepatic function and 6 had moderate hepatic impairment.

Conclusion: Patients with moderate hepatic impairment showed mildly increased AUC0-inf for rucaparib compared to patients with normal hepatic function. Although more patients with moderate hepatic impairment experienced TEAEs, only 2 TEAEs were considered treatment related. These results suggest no starting dose adjustment is necessary for patients with moderate hepatic impairment; however, close safety monitoring is warranted.

Keywords: Hepatic impairment; Pharmacokinetics; Poly(ADP-ribose) polymerase inhibitors; Rucaparib; Safety.

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Conflict of interest statement

N. Grechko, J. Beltman, E. Nash, J. Habeck, M. Liao, and J.J. Xiao are employees of Clovis Oncology and may own stock or have stock options in that company. Y. Drew is an employee of Newcastle University and has received royalty payments from Newcastle for her involvement in the development of rucaparib; she has served as an advisory board member and received research funding from Clovis Oncology. R. Dziadziuszko has received renumeration from AstraZeneca, Foundation Medicine, MSD, Novartis, Pfizer, Roche, Seattle Genetics, and Takeda. The other authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Mean (± SD) plasma concentration–time profile on a semi-log scale by hepatic function group (NCI-ODWG) for a rucaparib and b M324
See this image and copyright information in PMC

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