In vitro and in vivo pharmacokinetics, disposition, and drug-drug interaction potential of tinengotinib (TT-00420), a promising investigational drug for treatment of cholangiocarcinoma and other solid tumors
Early clinical trials of tinengotinib (TT-00420) have shown promising initial effectiveness against various refractory cancers, including relapsed cholangiocarcinoma resistant to fibroblast growth factor receptor (FGFR) inhibitors, castrate-resistant prostate cancer (CRPC), and HR+/HER2- as well as triple negative breast cancers (TNBC). To further assess its potential as a drug candidate, understanding its metabolism and pharmacokinetic properties is crucial.
This manuscript presents findings from investigations into tinengotinib’s in vitro permeability, plasma protein binding, metabolic stability, metabolite identification, and drug-drug interaction potential. Preclinical ADME (absorption, distribution, metabolism, and excretion) studies in rats and dogs were conducted using [14C]tinengotinib. Results indicate that tinengotinib exhibits high permeability and plasma protein binding, with distribution evenly between blood and plasma. Human liver microsome studies revealed no unique metabolites, and tinengotinib displayed moderate hepatic clearance.
Tinengotinib does not significantly inhibit or induce P450 enzymes at clinically relevant concentrations, suggesting minimal risk of drug-drug interactions involving key transporters. It demonstrated good oral bioavailability and dose-dependent exposure in both rats and dogs, with radioactivity primarily distributed in the gastrointestinal system and liver. Tinengotinib showed limited penetration across the blood-brain barrier.
In rats and dogs, unchanged drug (>89%) predominated in plasma, with over 93% of the dose eliminated via feces and less than 4% via renal excretion. CYP3A4 mainly mediates tinengotinib metabolism, with minor contributions from CYP2D6 and CYP2C8. Metabolic pathways include oxidation, oxidative cleavage of the morpholine ring, and conjugations with glucuronide and glutathione.
Overall, these preclinical pharmacokinetic findings support tinengotinib‘s advancement as a clinical candidate.