Evaluation of absorption, distribution, metabolism, and excretion of [(14)C]-rucaparib, a poly(ADP-ribose) polymerase inhibitor, in patients with advanced solid tumors.
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Liao M, Watkins S, Nash E, Isaacson J, Etter J, Beltman J, Fan R, Shen L, Mutlib A, Kemeny V, Papai Z, van Tilburg P, Xiao JJ
Evaluation of absorption, distribution, metabolism, and excretion of [(14)C]-rucaparib, a poly(ADP-ribose) polymerase inhibitor, in patients with advanced solid tumors.
Invest New Drugs. 2020 Jun;38(3):765-775. doi: 10.1007/s10637-019-00815-2. Epub 2019 Jun 27.
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- 31250355 [ View in PubMed]
- Abstract
Rucaparib, 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 [(14)C]-rucaparib 600 mg ( approximately 140 muCi). 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 approximately 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.
