Preclinical Pharmacokinetics and in vitro Metabolism of FHND5071, a Novel Selective RET Kinase Inhibitor.

BACKGROUND AND OBJECTIVES

Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase that plays a crucial role in tumorigenesis. FHND5071, a potent and selective RET kinase inhibitor, could exert antitumor effects by inhibiting RET autophosphorylation. The present work aims to profile the pharmacokinetics of FHND5071 in in vivo and in vitro experiments as a ground work for further clinical research.

METHODS

The absorption, distribution, metabolism, and excretion properties of FHND5071 were examined, along with metabolite production and cytochrome P450 (CYP) phenotyping assay. Additionally, plasma protein binding and pharmacokinetics in mice were investigated.

RESULTS

Microsomal stability assay corroborated moderate to high clearance of FHND5071, and the use of UPLC-Q-TOF-MS identified a total of six metabolites and suggested a possible metabolic pathway involving oxidation, demethylation, and N-dealkylation. Primary contributors to the CYP-mediated metabolism of FHND5071 were found to be CYP2C8 and CYP3A4, and FHND5071 displayed low permeability and acted as a substrate for the P-glycoprotein (P-gp). FHND5071 had a moderate to high binding in plasma and exhibited a moderate absorption degree (absolute bioavailability > 60%) The distribution of FHND5071 in mouse tissues was rapid (mostly peaking at 1-4 h) and wide (detectable in almost all tissues and organs), with the highest exposure in the spleen. A small fraction of FHND5071 was excreted via the urine and feces, and a presumed metabolic pathway involving 20 metabolites in mice is proposed.

CONCLUSION

Pharmacokinetic characteristics of FHND5071 were systemically profiled, which may lay the foundation for further clinical development as a drug candidate.