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Abstract
1. The disposition of tanzisertib [(1S,4R)-4-(9-((S)tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino) cyclohexanol], a potent, orally active c-Jun amino-terminal kinase inhibitor intended for treatment of fibrotic diseases was studied in rats, dogs and humans following a single oral dose of [14C]tanzisertib (Independent Investigational Review Board Inc., Plantation, FL).
2. Administered dose was quantitatively recovered in all species and feces/bile was the major route of elimination. Tanzisertib was rapidly absorbed (Tmax: 1–2 h) across all species with unchanged tanzisertib representing >83% of plasma radioactivity in dogs and humans, whereas <34% was observed in rats. Variable amounts of unchanged tanzisertib (1.5–32% of dose) was recovered in urine/feces across all species, the highest in human feces.
3. Metabolic profiling revealed that tanzisertib was primarily metabolized via oxidation and conjugation pathways, but extensively metabolized in rats relative to dogs/humans. CC-418424 (S-cis isomer of tanzisertib) was the major plasma metabolite in rats (38.4–46.4% of plasma radioactivity), while the predominant plasma metabolite in humans and dogs was M18 (tanzisertib-/CC-418424 glucuronide), representing 7.7 and 3.2% of plasma radioactivity, respectively. Prevalent biliary metabolite in rats and dogs, M18 represented 16.8 and 17.1% of dose, respectively.
4. In vitro studies using liver subcellular fractions and expressed enzymes characterized involvement of novel human aldo-keto reductases for oxido-reduction and UDP-glucuronosyltransferases for conjugation pathways.
Declaration of interest
All studies reported here were supported by Celgene and conducted by or under the supervision of Celgene employees. The authors report no conflicts of interest.