Absorption, Metabolism, and Excretion of Quizartinib (AC220), a FLT3 Tyrosine Kinase Inhibitor for Treatment of Acute Myeloid Leukemia, in Healthy Male Volunteers

Abstract 4327

Quizartinib (AC220) is an oral tyrosine kinase inhibitor that has shown promising activity in refractory/relapsed acute myeloid leukemia patients in a Phase 1 and a Phase 2 study. The absorption, metabolism, and excretion of quizartinib were characterized in healthy volunteers in a Phase 1 mass balance study. Six healthy males (mean ± SD age 29 ± 8.4 years) received a single oral dose of 60 mg quizartinib as a solution; approximately 1.6% of the total dose was labeled with ¹⁴C (approximately 100 μCi). Blood, plasma, urine, and feces were collected for 14 days (336 h) after dosing.

Maximum mean ± SD blood radioactivity concentrations, reached 4 h after dosing, were 296 ± 67.4 ng equivalents/g. Maximum blood radioactivity concentrations in individual subjects occurred 4 h after dosing and ranged from 228 to 397 ng equivalents/g.

Excretion of radioactivity was relatively consistent throughout the study. The maximum mean ± SD urinary concentration of radioactivity was 112 ± 52.3 ng equivalents/g at 8 to 24 hours after dosing, and the maximum mean ± SD fecal concentration of radioactivity was 51,100 ± 21,300 ng equivalents/g at 24 to 48 h after dosing. A mean ± SD of 1.64 ± 0.482% of the dose was recovered in urine, and 76.3 ± 6.23% was recovered in feces. The overall mean ± SD recovery of radioactivity in urine and feces was 78.0 ± 6.24% over the course of the study, with recovery from individual subjects ranging from 72.4% to 88.3%. Excretion of radioactivity was still ongoing at study completion (336 h). Recovery of <90% was not unexpected given the long half-life (approximately 3.5 days) of quizartinib.

The major radiolabeled components of plasma were unchanged quizartinib and the oxidative metabolite AC886. Five additional metabolites in plasma were identified by LC-MS but could not be identified by measurement of radioactivity, because of low levels. Eighteen radioactive peaks in urine were detected, representing less than 0.09% of the administered dose, but their putative structures could not be identified because of low levels.

Quizartinib was extensively metabolized, with the metabolites excreted primarily in feces, suggesting hepatobiliary excretion of radioactivity, non-biliary excretion into the gastrointestinal tract, or metabolism within the gastrointestinal tract. Forty-two radioactive peaks were detected in fecal extracts, of which unchanged quizartinib was a significant radioactive component (mean of 4.0% of the administered radioactive dose), and 15 metabolites, each representing a mean of 1.0% to 3.5% of the administered radioactive dose, were identified.

Quizartinib was predominantly metabolized by phase I biotransformations, as was evident by the absence of any conjugates of quizartinib or of oxidative metabolites under the analytical conditions used to profile plasma, urine, and feces. Quizartinib was metabolized by multiple biotransformation pathways, including oxidation, reduction, dealkylation, deamination, and hydrolysis, and by combinations of these pathways.

Quizartinib was well tolerated as a single 60 mg dose in this study. There were no clinically significant changes in vital signs, ECGs, or laboratory test results. Two subjects experienced adverse events. Grade 1 dry skin in 1 subject was considered to be unrelated to study treatment, and Grade 1 diarrhea in 1 subject was considered to be possibly related to treatment.

The results of this study indicated that, in humans, quizartinib was orally available and predominantly eliminated in feces, with renal clearance as a minor elimination route, and that AC886 was the only major metabolite in the circulation.