title: Clearance Prediction of Targeted Covalent Inhibitors by In Vitro-In Vivo Extrapolation of Hepatic and Extrahepatic Clearance Mechanisms.
abstract: The concept of target-specific covalent enzyme inhibitors appears attractive from both an efficacy and a selectivity viewpoint considering the potential for enhanced biochemical efficiency associated with an irreversible mechanism. Aside from potential safety concerns, clearance prediction of covalent inhibitors represents a unique challenge due to the inclusion of nontraditional metabolic pathways of direct conjugation with glutathione (GSH) or via GSH S-transferase-mediated processes. In this article, a novel pharmacokinetic algorithm was developed using a series of Pfizer kinase selective acrylamide covalent inhibitors based on their in vitro-in vivo extrapolation of systemic clearance in rats. The algorithm encompasses the use of hepatocytes as an in vitro model for hepatic clearance due to oxidative metabolism and GSH conjugation, and the use of whole blood as an in vitro surrogate for GSH conjugation in extrahepatic tissues. Initial evaluations with clinical covalent inhibitors suggested that the scaling algorithm developed from rats may also be useful for human clearance prediction when species-specific parameters, such as hepatocyte and blood stability and blood binding, were considered. With careful consideration of clearance mechanisms, the described in vitro-in vivo extrapolation approach may be useful to facilitate candidate optimization, selection, and prediction of human pharmacokinetic clearance during the discovery and development of targeted covalent inhibitors.
authors: Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.).
authors: Louis
authors: L
authors: Leung
authors: Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.).
authors: Xin
authors: X
authors: Yang
authors: Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.).
authors: Timothy J
authors: TJ
authors: Strelevitz
authors: Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.).
authors: Justin
authors: J
authors: Montgomery
authors: Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.).
authors: Matthew F
authors: MF
authors: Brown
authors: Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.).
authors: Michael A
authors: MA
authors: Zientek
authors: Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.).
authors: Christopher
authors: C
authors: Banfield
authors: Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.).
authors: Adam M
authors: AM
authors: Gilbert
authors: Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.).
authors: Atli
authors: A
authors: Thorarensen
authors: Pfizer Worldwide Research and Development; Pharmacokinetics, Dynamics and Metabolism, Groton, Connecticut (L.L., X.Y., T.J.S.), Andover, Massachusetts (M.E.D.), and La Jolla, California (M.A.Z.); Medicinal Chemistry, Cambridge, Massachusetts (A.T.), and Groton, Connecticut (J.M., M.F.B., A.M.G.); and Clinical Research, Cambridge, Massachusetts (C.B.) martin.dowty@pfizer.com.
authors: Martin E
authors: ME
authors: Dowty
mesh_terms: D000465:Algorithms; D000818:Animals; D004353:Drug Evaluation, Preclinical; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008657:Metabolic Clearance Rate; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000097:blood / Q000378:metabolism*; D010949:Plasma / Q000378:metabolism*; D011237:Predictive Value of Tests; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D004364:Pharmaceutical Preparations; D047428:Protein Kinase Inhibitors; D005978:Glutathione