Abstract
The present article summarizes MIST studies on a glucokinase activator PF-04937319, which is under development for the treatment of T2DM. Metabolic profiling in rat, dog and human hepatocytes revealed that PF-04937319 is metabolized via oxidative (major) and hydrolytic pathways (minor). N-Demethylation to metabolite M1 was the major metabolic fate of PF-04937319 in human (but not rat or dog) hepatocytes, and was catalyzed by CYP3A and CYP2C isoforms. Qualitative examination of circulating metabolites in humans at the 100 mg and 300 mg doses from a 14-day multiple dose study revealed unchanged parent drug and M1 as principal components. Because M1 accounted for 65% of the drug related material at steady state, an authentic standard was synthesized and used for comparison of steady state exposures in human and the 3–month safety studies in rats and dogs at the NOAEL. Although circulating levels of M1 were very low in beagle dogs and female rats, adequate coverage was obtained in terms of total Cmax (~7.7x and 1.8x) and AUC (3.6x and 0.8x AUC) relative to the 100 mg and 300 mg, doses, respectively in male rats. Examination of primary pharmacology revealed M1 was less potent as a glucokinase activator than the parent drug (compound PF-04937319:EC50=0.17 μM; M1:EC50=4.69 μM). Furthermore, M1 did not inhibit major human CYP enzymes (IC50>30 μM), was negative in the Salmonella Ames assay, with minimal off-target pharmacology, based on CEREP broad ligand profiling. Insights gained from this analysis should lead to a more efficient and focused development plan for fulfilling MIST requirements with PF-04937319.
- cytochrome P450
- drug design
- drug-drug interactions
- hepatocytes
- human/clinical
- mass spectrometry/MS
- metabolite identification
- pharmacokinetics
- The American Society for Pharmacology and Experimental Therapeutics