Biotransformation and disposition characteristics of HSK7653, a novel long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes

Aim: To investigate the metabolism and disposition characteristics of HSK7653 in healthy male Chinese participants.

Methods: A single oral dose of 80 μCi (25 mg) [¹⁴C]HSK7653 capsules was administered to six healthy participants, and blood, plasma, urine and faeces were collected. Quantitative and qualitative analysis was conducted to investigate the pharmacokinetics, blood-to-plasma ratio, mass balance and metabolism of HSK7653.

Results: The drug was well absorbed and reached a maximum concentration at 1.25 h. The drug-related components (HSK7653 and its metabolites) were eliminated slowly, with a half-life (t_1/2) of 111 h. Unchanged HSK7653 contributed to more than 97% of the total radioactivity in all plasma samples. The blood-to-plasma ratio (0.573-0.845) indicated that HSK7653 did not tend to distribute into blood cells. At 504 h postdose, up to 95.9% of the dose was excreted, including 79.8% in urine and 16.1% in faeces. Most of the radioactivity (75.5% dose) in excreta was unchanged HSK7653. In addition, nine metabolites were detected in urine and faeces. The most abundant metabolite was M6-2, a dioxidation product of HSK7653, which accounted for 4.73% and 2.63% of the dose in urine and faeces, respectively. The main metabolic pathways of HSK7653 in vivo included oxidation, pyrrole ring opening and sulphonamide hydrolysation.

Conclusion: HSK7653 was well absorbed, slightly metabolized and slowly excreted in humans. The high plasma exposure and long t_1/2 of HSK7653 may contribute to its long-lasting efficacy as a long-acting dipeptidyl peptidase-4 inhibitor.