Clinical Pharmacology Profile of Pacritinib (PAC), a Novel JAK2/FLT3 Inhibitor

Introduction: PAC is a kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R that does not inhibit JAK1. PAC has demonstrated activity in phase (Ph) 1-3 clinical studies. Nonclinical and clinical pharmacokinetic (PK) and pharmacodynamic studies support a 400 mg QD oral dosing regimen in ongoing Ph 3 studies in myelofibrosis. Here we present PK data from a series of Ph 1 studies of PAC.

Methods: Seven Ph 1 studies were conducted in healthy subjects receiving a single 100, 200, or 400 mg dose of PAC. In an ADME mass balance study, [¹⁴ C]-PAC was administered to characterize routes of disposition. Separate drug interaction studies were conducted to assess effects of a strong CYP3A4 inhibitor (clarithromycin) or strong pan-CYP450 inducer (rifampin) on PAC PK. Cardiac safety of PAC was evaluated in a thorough QT (TQT) study. Food-effect, dose proportionality, and relative bioavailability studies were also conducted.

Results: 140 subjects across 7 studies received single doses of PAC 100-400 mg. PK parameters of PAC 400 mg are presented in the Table (n=12). Following administration of single 100-400 mg PAC doses under fasted conditions, systemic exposure increased in a linear, but less than dose proportional manner. Among identified metabolites, the 2 major metabolites (M1, M2) exhibit relatively low pharmacological potency and are unlikely to contribute to PAC activity. Following a 400 mg single dose of [¹⁴ C]-PAC, the parent compound was the predominant moiety in plasma. Mean radioactivity recovery in urine = 3.22% of administered dose with intact PAC excreted in urine = 0.12% of administered dose. Of all 9 metabolites formed, M7, a glucuronidated metabolite, was the predominant radioactive component (3.03% of administered dose) excreted in urine. Mean radioactivity recovery in feces = 85.46% of administered dose and M2 (O- dealkylation metabolite) was the predominant component (24.08% of administered dose). When co-administered with clarithromycin (CYP3A4 inhibitor), PAC exposure increased with mean C_max and AUC approximately 1.3- and 1.8-fold higher, respectively, with a similar mean t_1/2 vs PAC alone. Co-administration with rifampin, a strong CYP3A4 inducer, reduced mean PAC C_max and AUC by 51% and 87%, respectively vs PAC alone. Median T_max was similar when co-administered with rifampin vs PAC alone (5-6 h), but t_1/2 was shortened by approximately 65% (PAC: 43.3 h; PAC + rifampin: 15.1 h). Administration of single oral doses of PAC 400 mg in a placebo- and moxifloxacin-controlled TQT study had no clinically relevant effects on ECG parameters, including heart rate. There was no effect on QT prolongation (mean QTcF change <10 msec) and a small but non-clinically significant shortening in the placebo-corrected change in QTcF below 0 msec in the first 12 h post-dose. Across all clinical pharmacology studies, PAC was tolerable (primarily grade 1 gastrointestinal AEs), consistent with the PAC clinical safety profile to date.

Conclusions: PAC exhibits moderate oral bioavailability and is eliminated primarily through metabolism and biliary excretion. Minimal excretion occurs via renal clearance, indicating dosage adjustment is unlikely to be warranted in renal impairment. Increase in PAC exposure is limited when co-administered with a strong CYP3A4 inhibitor, unlikely necessitating dosage adjustments. There is marked reduction in systemic exposure when co-administered with a strong CYP450 inducer and co-administration should therefore be avoided due to potential for negative impact on efficacy. PAC was not found to cause QT prolongation, suggesting favorable cardiac safety. Single 100-400 mg doses of PAC were well tolerated in healthy volunteers in these studies. Overall, PAC exhibited a favorable clinical pharmacology profile supportive of its safety and tolerability at clinical dose levels.