Work

Human absorption, distribution, metabolism, excretion, and reaction phenotyping of ervogastat (PF-06865571), a diacylglycerol O-acyltransferase 2 inhibitor

Year: 2026

Type: article

Abstract: Ervogastat (PF-06865571) is a potent and selective small-molecule inhibitor of diacylglycerol- O -acyltransferase-2 currently in clinical development for treating metabolic dysfunction-associated steatohepatitis with liver fibrosis. A fixed-sequence two-period 14 C-microtracer cross-over study was used to determine a comprehensive and quantitative overview of the total disposition of ervogastat after oral and intravenous administration. From these studies, ervogastat was determined to have a systemic clearance of 23.9 L/h, a volume of distribution of 38.8 L, extent of oral absorption of ∼93%, time to maximum plasma concentration of ∼3.0 hours, and absolute oral bioavailability of ∼75%. The plasma half-lives of both ervogastat and total radioactivity were similar, with no indication of long-lived metabolites. The total recovery of [ 14 C]ervogastat after oral administration was 79.0 ± 16.7%, with 48.9 ± 16.3% in the urine and 30.1 ± 2.9% in the feces. Ervogastat metabolites observed in human plasma, urine and feces generally can be assigned as originating from one of four primary metabolic pathways: amide bond hydrolysis (M2); tetrahydrofuran oxidation (M4/M5); O -deethylation (M1); and direct glucuronidation (584). The major circulating drug-related components were ervogastat (43.8%), M2 (36.6%) and M6 (11.3%). The major drug-related components detected in urine were M2 (24.9%) and coeluting M6 (des-ethyl sulfate), M7 (des-ethyl amide hydrolysis) and 584 (11.4%). In the feces the predominant drug-related products were coeluting M4 and 426 (10.0%), M2 (7.0), M7 (6.3%) and M1 (4.5%). Reaction phenotyping was carried out using a subsequent qualitative followed by quantitative approach identifying CYP3A metabolism as the predominant route of in vitro metabolism. As assignment of metabolic pathways in the hADME study was complicated by chromatographically coeluting metabolites or metabolites arising from multiple possible primary pathways, fractional clearance ranges were derived by assigning metabolites to only one primary pathway at a time to represent a potential permutation followed by evaluation of all possible permutations. This novel approach allowed us to overcome the aforementioned confounding issues and, along with in vitro chemical inhibition results, permitted the assignment of the various metabolic pathways and enzymes involved in the metabolism of ervogastat.NCT04866225

Source: Drug Metabolism and Disposition

DOI: 10.1016/j.dmd.2026.100286