Human Mass Balance and Metabolite Profiling of [14C]‐Pamiparib, a Poly (ADP‐Ribose) Polymerase Inhibitor, in Patients With Advanced Cancer
| Autor: | Heather Zhang, Dan Su, Daniel H. Palmer, Zhiyu Tang, Claudia Andreu-Vieyra, Song Mu, Srikumar Sahasranaman, Richard Fitzgerald |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
medicine.medical_specialty CYP3A Metabolite Cmax Pharmaceutical Science DNA repair Original Manuscript Urine Poly(ADP-ribose) Polymerase Inhibitors 030226 pharmacology & pharmacy Excretion Cytochrome P-450 CYP2C8 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics metabolite identification Internal medicine Neoplasms medicine Cytochrome P-450 CYP3A Humans Pharmacology (medical) Fluorenes biology business.industry pamiparib Cytochrome P450 Metabolism Articles Middle Aged Endocrinology Phenotype chemistry 030220 oncology & carcinogenesis biology.protein Female absorption/metabolism/excretion business pharmacokinetics Half-Life |
| Zdroj: | Clinical Pharmacology in Drug Development |
| ISSN: | 2160-7648 2160-763X |
| Popis: | Pamiparib, a selective poly (ADP‐ribose) polymerase 1/2 inhibitor, demonstrated tolerability and antitumor activity in patients with solid tumors at 60 mg orally twice daily. This phase 1 open‐label study (NCT03991494; BGB‐290‐106) investigated the absorption, metabolism, and excretion (AME) of 60 mg [14C]‐pamiparib in 4 patients with solid tumors. The mass balance in excreta, blood, and plasma radioactivity and plasma pamiparib concentration were determined along with metabolite profiles in plasma, urine, and feces. Unchanged pamiparib accounted for the most plasma radioactivity (67.2% ± 10.2%). Pamiparib was rapidly absorbed with a median time to maximum plasma concentration (Cmax) of 2.00 hours (range, 1.00‐3.05 hours). After reaching Cmax, pamiparib declined in a biphasic manner, with a geometric mean terminal half‐life (t1/2) of 28.7 hours. Mean cumulative [14C]‐pamiparib excretion was 84.7% ± 3.5%. Pamiparib was mainly cleared through metabolism, primarily via N‐oxidation and oxidation of the pyrrolidine ring. A dehydrogenated oxidative product (M3) was the most abundant metabolite in biosamples. A mean of 2.11% and 1.11% of [14C]‐pamiparib was excreted as unchanged pamiparib in feces and urine, respectively, indicating near‐complete absorption and low renal clearance of parent drug. Cytochrome P450 (CYP) phenotyping demonstrated CYP2C8 and CYP3A involvement in pamiparib metabolism. These findings provide an understanding of pamiparib AME mechanisms and potential drug‐drug interaction liability. |
| Databáze: | OpenAIRE |
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