Abstract
SummaryRucaparib, a poly(ADP-ribose) polymerase inhibitor, is licensed for use in recurrent ovarian, fallopian tube, or primary peritoneal cancer. We characterized the absorption, distribution, metabolism, and elimination of rucaparib in 6 patients with advanced solid tumors following a single oral dose of [14C]-rucaparib 600 mg (≈140 μCi). Total radioactivity (TRA) in blood, plasma, urine, and feces was measured using liquid scintillation counting. Unchanged rucaparib concentrations in plasma were determined using validated liquid chromatography with tandem mass spectrometry. Maximum concentration (Cmax) of TRA and unchanged rucaparib in plasma was 880 ng Eq/mL and 428 ng/mL, respectively, at approximately 4 h post dose; terminal half-life was >25 h for both TRA and rucaparib. The plasma TRA-time profile was parallel to yet higher than that of rucaparib, suggesting the presence of metabolites in plasma. Mean blood:plasma ratio of radioactivity was 1.0 for Cmax and 0.8 for area under the concentration-time curve from time zero to infinity. Mean postdose recovery of TRA was 89.3% over 12 days (71.9% in feces; 17.4% in urine). Unchanged rucaparib and M324 (oxidative metabolite) were the major components in plasma, contributing to 64.0% and 18.6% of plasma radioactivity, respectively. Rucaparib and M324 were the major rucaparib-related components (each ≈7.6% of dose) in urine, whereas rucaparib was the predominant component (63.9% of dose) in feces. The high fecal recovery of unchanged rucaparib could be attributed to hepatic excretion and/or incomplete oral absorption. Overall, these data suggest that rucaparib is eliminated through multiple pathways, including metabolism and renal and biliary excretion.
Highlights
Rucaparib is a potent, oral, small molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1, PARP2, and PARP3 [1]
In the European Union, rucaparib is approved as a monotherapy treatment for adult patients with platinum-sensitive, relapsed or progressive, BRCA-mutated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or Invest New Drugs (2020) 38:765–775 more prior lines of platinum-based chemotherapy and who are unable to tolerate further platinum-based chemotherapy [4]
Rucaparib is approved in both the United States and the European Union as a monotherapy maintenance treatment for adult patients with recurrent, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy [1, 4]
Summary
Oral, small molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1, PARP2, and PARP3 [1]. In the United States, rucaparib is approved as a monotherapy treatment for patients with BRCA mutation (germline and/or somatic)–associated advanced ovarian cancer who have been treated with two or more chemotherapies [1]. In the European Union, rucaparib is approved as a monotherapy treatment for adult patients with platinum-sensitive, relapsed or progressive, BRCA-mutated (germline and/or somatic) epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or Invest New Drugs (2020) 38:765–775 more prior lines of platinum-based chemotherapy and who are unable to tolerate further platinum-based chemotherapy [4]. Rucaparib is approved in both the United States and the European Union as a monotherapy maintenance treatment for adult patients with recurrent, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy [1, 4]. Rucaparib is being investigated for treatment of other solid tumors, including prostate cancer (NCT02952534 and NCT02975934)
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