Tebapivat: Pharmacokinetic Properties in Preclinical Species and Pharmacodynamic Responses Associated With Pyruvate Kinase Activation in Wild-Type Mice

Abstract

The investigation of pyruvate kinase activating drugs is expanding into previously untested diseases as the benefits of increasing glycolytic flux within pyruvate kinase-expressing tissues emerges. Recently, we reported the discovery of allosteric activator tebapivat, an investigational drug currently being studied in lower-risk myelodysplastic syndrome and sickle cell disease patients. This new compound is chemically distinct from the other marketed or investigational pyruvate kinase activators and demonstrated pharmacodynamic effects at low plasma exposures in healthy volunteers. To further distinguish the tebapivat chemotype, this report describes the pharmacokinetic and pharmacodynamic studies used to advance tebapivat to the clinic. Good oral bioavailability and low clearance were observed across animal species, but corrections for in vitro species differences in plasma binding were necessary to predict human clearance from animals. In mouse pharmacodynamic studies, blood biomarkers of pyruvate kinase activation reached near-maximum effect-area-under-the-curve changes at low oral dose (∼0.03 mg/kg). Lastly, we observed long-lived blood pharmacodynamics (up to 14 d), non-linear red blood cell partitioning, and the convergence of terminal blood drug concentrations from different doses in mice. We hypothesize these findings are most consistent with target-mediated drug disposition and are a result of the long residence time of tebapivat on its pharmacological target pyruvate kinase in red blood cells, and thus represents a subtle saturable property related to the high potency of tebapivat.