Abstract
Venetoclax (also known as ABT-199) is a B-cell lymphoma-2 (Bcl-2) family protein inhibitor and is currently in clinical development for the treatment of chronic lymphocytic leukaemia (CLL) and other hematological malignancies. The objective of this study was to characterize the absorption, metabolism, and excretion of venetoclax in humans. Following a single oral dose of 200 mg (100 μ - Ci) of [14C]venetoclax to four healthy volunteers, recovery of total radioactive dose was 100% (± 5%), with feces being the major route of elimination of the administered dose, whereas urinary excretion was minimal (<0.1%). The extent of absorption was estimated to be at least 65%. Venetoclax was primarily cleared by hepatic metabolism (~66% of the administered dose). ~33% of the administered dose was recovered as parent drug and its nitro reduction metabolite M30 in feces, which is likely due to unabsorbed parent drug. Biotransformation of venetoclax in human primarily involves enzymatic oxidation on the dimethyl cyclohexenyl moiety, followed by sulfation and/or nitro reduction. Nitro reduction metabolites were likely formed by gut bacteria. The metabolite profile in pooled plasma samples showed that unchanged venetoclax was the major drug-related material in circulation, representing 72.8% of total plasma radioactivity. M27 (oxidation at the 6 position of cyclohexenyl ring followed by cyclization at the α-carbon of piperazine ring) was identified as a major metabolite representing 12% of total drug related material. M27 was primarily formed by CYP3A4. Steady-state plasma concentrations of M27 measured by LC-MS analysis in human and preclinical species used for safety testing suggested that M27 is a disproportionate human metabolite. M27 is not expected to have clinically relevant on- or off-target pharmacological activities. In summary, the study characterized venetoclax metabolites in circulation and feces and the primary elimination pathway of venetoclax in human.
- cytochrome P450
- drug absorption
- HPLC
- mass spectrometry/MS
- metabolite disposition
- metabolite identification
- reductases
- The American Society for Pharmacology and Experimental Therapeutics