Abstract CT159: Investigation of the absorption, metabolism, excretion, and mass balance of [14C]-pacritinib in healthy subjects: a phase I study

Abstract

Abstract Introduction: Dysregulation in tyrosine kinase signaling has been implicated in development of hematologic malignancies including myelofibrosis and lymphomas. Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, CSF1R, and IRAK1. In mouse distribution studies of radiolabeled pacritinib, ∼91% of administered dose was recovered in the feces, suggesting an important role for biliary elimination in clearance of pacritinib. This phase 1 trial investigated clearance pathways, excretion, pharmacokinetics, and recovery of pacritinib, its major metabolites, and total radioactivity in healthy volunteers. Methods: Healthy male volunteers aged 18-55 y were eligible for inclusion. Study volunteers received a single 400 mg dose of pacritinib capsules plus a single dose of [14C]-pacritinib (100 μCi radioactivity per <1 mg of pacritinib as a 30 mL suspension). Blood, urine, and feces were sampled predose and up to 42 days postdose. Pacritinib and metabolites were identified using HPLC-MS/MS/radio flow-through detector (RFD), high resolution mass spectrometry, and authentic metabolite standards. Results: Six subjects were enrolled and received [14C]-pacritinib. Peak radioactivity in plasma was reached approximately 2 h following administration. Mean apparent volume of distribution and apparent clearance in plasma were 137 L and 1.73 L/h, respectively. Elimination half-life for total radioactivity in plasma was 55.1 h. Twelve pacritinib metabolites were identified: M1, M2, M3, M5, M6, M7, M8, M9, M12, M13, M14, and M14a and reflected metabolic pathways including oxidation, N-dealkylation, O-dealkylation, hydrolysis, and dehydrogenation. Pacritinib was the predominant radioactive component (72%) recovered in plasma from 0.5-120 h with mean maximum concentration (Cmax) of 4117.2 ng/mL. Mean Cmax for M2, M1, M3, and M8 were 887.0, 854.5, 292.3, and 148.6 ng/mL respectively. Mean metabolite exposure ratios for major metabolites, M1 and M2, in plasma relative to pacritinib were 0.0963 and 0.105, respectively. Mean recovery of radioactivity in urine (0-48 h) was 3.22% of administered dose; M7, a glucuronidated metabolite, was the predominant radioactive component (3.03% of administered dose). Pacritinib recovered in urine accounted for 0.12% of administered dose. From 0-240 h postdose, mean recovery of radioactivity in feces was 85.5% of administered dose. Pacritinib was detected by MS in fecal samples, but not by RFD. Metabolite M2 was the predominant radioactive fecal component, (24.1% of administered dose). Five individuals (83.3%) reported 9 total adverse events (AEs); all AEs were grade 1 and included diarrhea (5 events in 4 individuals) and nausea (1 event in 1 individual). There were no clinically significant abnormalities in vital signs, ECG, or by physical examination. Conclusions: Following oral administration, pacritinib was the predominant moiety recovered in plasma. Pacritinib was extensively metabolized; major metabolites (M1, oxidation; M2, dealkylation) have relatively low pharmacological potency and are unlikely to substantially contribute to the activity of pacritinib. Intact pacritinib was minimally excreted in urine and feces. Most radioactivity was recovered as metabolites in feces, suggesting extensive biliary clearance and hepatic metabolism of pacritinib. Citation Format: Suliman Al-Fayoumi, Sherri Amberg, Huafeng Zhou, Lindsey Millard, Jack W. Singer, James P. Dean. Investigation of the absorption, metabolism, excretion, and mass balance of [14C]-pacritinib in healthy subjects: a phase I study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT159.