Human Mass Balance and Metabolite Profiling of [¹⁴C]‐Pamiparib, a Poly (ADP‐Ribose) Polymerase Inhibitor, in Patients With Advanced Cancer

Abstract

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.

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

“…So far, most DDRi have been directly radiolabeled with 123 I-, 131 I-, 18 F- and 211 At-radionuclides. Only one analog of olaparib was 64 Cu-radiolabeled following conjugation of a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) moiety, allowing for PET imaging of mesothelioma [ 29 , 40 , 49 , 50 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ].…”

“…PARP radiopharmaceuticals in a preclinical phase that are worth exploring in GB include [ 14 C]-pamiparib and [ 64 Cu]-DOTA-PARPi. The ADME of [ 14 C]-pamiparib was evaluated in four patients with advanced cancer and indicated near-complete absorption and low renal clearance of the parent drug [ 74 ]. [ 64 Cu]-DOTA-PARPi showed potential in mesothelioma-bearing animal models [ 64 ].…”

“… Radiopharmaceuticals targeting DDR kinases studied in various cancer types (for details see Table S2 ). Ataxia-telangiectasia mutated (ATM), ATM-RAD3-related protein (ATR), checkpoint kinase-1 and -2 (CHK1/2), DDR kinase inhibitor (DDRi), DNA-dependent protein kinase (DNA-PK), poly (ADP-ribose) polymerase-1 and -2 (PARP) [ 29 , 40 , 49 , 50 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ]. …”