PF-04991532 / Pfizer - LARVOL DELTA

Chronic Glucokinase Activator treatment activates liver Carbohydrate Response Element binding protein and improves hepatocyte ATP homeostasis during substrate challenge. (PubMed, Diabetes Obes Metab) - "Chronic GKA treatment of C57BL/6 mice for 8 weeks activates liver ChREBP and improves the resilience of hepatocytes to compromised ATP homeostasis during high-substrate challenge. These changes are associated with raised mRNA levels of ChREBP-β and both catalytic subunits of AMP-activated protein kinase."

Journal • Diabetes • Hepatocellular Cancer • Metabolic Disorders • Solid Tumor • Type 2 Diabetes Mellitus • AMPK

Effect of hepatic OATP1B inhibition and chronic kidney disease on the pharmacokinetics of a liver-targeted glucokinase activator: A model-based evaluation. (PubMed, Clin Pharmacol Ther) - "Cyclosporine (600 mg single dose) increased mean area under the plasma curve (AUC) of PF-04991532 by approximately threefold in healthy subjects. Mechanistic evaluation of the clinical data suggest reduced hepatic OATPs (~35%) and renal OAT3 (80-90%) function with renal impairment. This study illustrates the adequacy and utility of PBPK approach in assessing impact of drug interactions and kidney dysfunction on transporter-mediated disposition."

Journal • PK/PD data • Chronic Kidney Disease • Nephrology • Renal Disease

Study to evaluate the effect of renal impairment on the pharmacokinetics of PF-04991532 (clinicaltrials.gov) - P1, N=27; Recruiting -> Completed

Trial completion • Diabetes

Pfizer pipeline (Pfizer) - P2 development for PF-04991532 in type 2 diabetes discontinued since May 10, 2012

Discontinued • Diabetes

Metabolism and Excretion of (S)-6-(3-Cyclopentyl-2-(4-trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid (PF-04991532), a Hepatoselective Glucokinase Activator, in Humans: Confirmation of the MIST Potential Noted in First-in-Human Metabolite Scouting Studies. (PubMed, Xenobiotica) - "4. The present results are in excellent agreement with our previously generated metabolite scouting data, which provided preliminary evidence for the disproportionate metabolism of PF-04991532 in humans."

Journal • P1 data