Pharmacokinetics and ADME Characterization After Oral and Intravenous Administration of [14C]-Ziftomenib in Healthy Male Participants

Abstract

Ziftomenib, a potent, selective inhibitor that binds menin at the lysine methyltransferase 2 interaction site, has demonstrated promising clinical activity with manageable toxicity in heavily pretreated patients with acute myeloid leukemia (AML) and nucleophosmin 1 mutations. This phase 1, open-label study characterized the absorption, metabolism, excretion, and bioavailability of ziftomenib in healthy men and comprised two parts. In part A, a single oral dose of ziftomenib 400 mg (containing 250 μCi [¹⁴C]-ziftomenib) was given to evaluate routes and rates of elimination, total radioactivity, and other pharmacokinetic parameters. In part B, a single oral dose of ziftomenib 400 mg followed by an intravenous dose of ziftomenib < 100 μg (containing 1 μCi [¹⁴C]-ziftomenib) was administered to evaluate absolute bioavailability (both n = 8 patients). A median t_max of 3.5 h and an elimination t_1/2 of 61.5 h demonstrated rapid ziftomenib absorption and enabled once-daily dosing. Total radioactivity recovery was 89.7% in feces and 0.5% in urine over 480 h. Absolute bioavailability of 12.9% was observed. Ziftomenib was primarily metabolized by oxidation, N-demethylation, and N-dealkylation, with 19 metabolites recovered in plasma. All metabolites were considered minor (< 10% of total drug-related exposure). Ziftomenib was the most abundant plasma component (> 10% of total drug-related exposure). In conclusion, ziftomenib underwent limited metabolism following absorption and was primarily excreted as unchanged parent drug in feces. Ziftomenib was well tolerated with no new safety concerns in healthy men. Considering the pharmacokinetic profile and manageable safety outcomes, these findings support further clinical investigation of ziftomenib as treatment for AML.