Human Pharmacokinetics of AC220, a Potent and Selective Class III Receptor Tyrosine Kinase Inhibitor.

Abstract

Abstract Introduction: Activating mutations in FLT3 are present in a significant fraction of acute myeloid leukemia (AML) cases. Patients with FLT3 mutations have a significantly worse prognosis than patients with wild type FLT3, suggesting that the activated kinase is a driver of the disease. AC220 is a novel class III receptor tyrosine kinase (RTK) inhibitor. It has highly potent activity against FLT3 and is highly selective for wild type and mutant FLT3 and other class III RTKs, including KIT, CSF1R/FMS, RET and PDGFR. AC220 is currently in a phase I clinical study for relapsed or refractory AML patients. Human pharmacokinetic (PK) data from early cohorts are presented along with the preclinical profile in support of the rationale for the clinical evaluation of AC220 in AML. Methods: Cellular efficacy of AC220 was evaluated in the FLT3-dependent human leukemia cell line MV4;11. This cell line was implanted in a mouse xenograft model, which was used to assess animal efficacy. In preclinical studies, pharmacokinetics were determined in rats and dogs. The clinical study is a phase I, first-in-man, multi-center, open label, sequential dose escalation study. AC220 is administered once daily as an oral solution for 14 days with a starting dose of 12 mg. At least three centers in the U.S. enrolled AML patients into three-patient cohorts. Results: AC220 inhibits proliferation of MV4;11 cells with subnanomolar potency (IC50 = 0.3 nM). In the mouse MV4;11 xenograft model, tumor regression is observed at 3 mg/kg (9 mg/m2, p.o., qd), and tumor growth inhibition at 1 mg/kg (3 mg/m2, p.o., qd). The terminal half-life is 5.7 hours in rats and 5.9 hours in dogs. In the clinical study, one male and two female patients were enrolled into cohort 1. The weight range for these patients is 77.9 to 101.27 kg. The average plasma concentrations at the 12 mg dose are 11.2 ng/mL at day 1, 37.9 ng/mL at day 8 and 42.9 ng/mL (0.06 μM) at steady state (by day 15), with an apparent terminal half-life of at least 2.8 days. Inter-patient variability of steady state plasma concentrations within the 3-patient cohort is low. Conclusions: At the human dose of 12 mg, AC220 is well tolerated and absorbed. It has a long terminal half-life and the inter-patient pharmacokinetic variability is low. Steady state is predicted to be reached within 8 to 14 days with minor peaks and troughs. There is a strong correlation between efficacy in the mouse model and AC220 plasma levels (adjusted for plasma protein binding) relative to potency in the MV4;11 cell-based assay. At the human dose of 12 mg (average 5.2 mg/m2), the plasma level of AC220 at steady state (0.06 μM, when adjusted for plasma protein binding) is approximately twofold higher than the MV4;11 cell IC50. Continued exploration in patients is warranted to determine the role of AC220 in the treatment of AML.