title: Mechanistic investigation of the preclinical pharmacokinetics and interspecies scaling of PF-05231023, a fibroblast growth factor 21-antibody protein conjugate.
abstract: PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analog, was generated by covalently conjugating two engineered [des-His1, Ala129Cys]FGF21 molecules to a nontargeting human IgG1 κ scaffold. The pharmacokinetics (PK) of PF-05231023 after i.v. and s.c. administration was evaluated in rats and monkeys using two enzyme-linked immunosorbent assays with high specificity for biologically relevant intact N termini (NT) and C termini (CT) of FGF21. Intact CT of FGF21 displayed approximately 5-fold faster systemic plasma clearance (CL), an approximately 2-fold lower steady-state volume of distribution, and at least 5-fold lower bioavailability compared with NT. In vitro serum stability studies in monkeys and humans suggested that the principal CL mechanism for PF-05231023 was degradation by serum proteases. Direct scaling of in vitro serum degradation rates for intact CT of FGF21 underestimated in vivo CL 5-fold, 1.4-fold, and 2-fold in rats, monkeys, and humans, respectively. The reduced steady-state volume of distribution and the bioavailability for intact CT relative to NT in rats and monkeys were compatible with proteolytic degradation occurring outside the plasma compartment via an unidentified mechanism. Human CL and PK profiles for intact NT and CT of FGF21 were well predicted using monkey single-species allometric and Dedrick scaling. Physiologically based pharmacokinetic models incorporating serum stability data and an extravascular extraction term based on differential bioavailability of intact NT and CT of FGF21 in monkeys improved accuracy of human PK predictions relative to Dedrick scaling. Mechanistic physiologically based pharmacokinetic models of this nature may be highly valuable for predicting human PK of fusion proteins, synthetically conjugated proteins, and other complex biologics.
authors: Pfizer Inc., Groton, Connecticut (C.G., C.V., Ju.L., K.P., M.R., A.L.); and Pfizer Inc., Cambridge, Massachusetts (N.-P.N., Je.L., R.A.C., Y.W.).
authors: Craig
authors: C
authors: Giragossian
authors: Pfizer Inc., Groton, Connecticut (C.G., C.V., Ju.L., K.P., M.R., A.L.); and Pfizer Inc., Cambridge, Massachusetts (N.-P.N., Je.L., R.A.C., Y.W.).
authors: Chandra
authors: C
authors: Vage
authors: Pfizer Inc., Groton, Connecticut (C.G., C.V., Ju.L., K.P., M.R., A.L.); and Pfizer Inc., Cambridge, Massachusetts (N.-P.N., Je.L., R.A.C., Y.W.).
authors: Jun
authors: J
authors: Li
authors: Pfizer Inc., Groton, Connecticut (C.G., C.V., Ju.L., K.P., M.R., A.L.); and Pfizer Inc., Cambridge, Massachusetts (N.-P.N., Je.L., R.A.C., Y.W.).
authors: Kathleen
authors: K
authors: Pelletier
authors: Pfizer Inc., Groton, Connecticut (C.G., C.V., Ju.L., K.P., M.R., A.L.); and Pfizer Inc., Cambridge, Massachusetts (N.-P.N., Je.L., R.A.C., Y.W.).
authors: Nicole
authors: http://orcid.org/0000-0003-0695-7965
authors: N
authors: Piché-Nicholas
authors: Pfizer Inc., Groton, Connecticut (C.G., C.V., Ju.L., K.P., M.R., A.L.); and Pfizer Inc., Cambridge, Massachusetts (N.-P.N., Je.L., R.A.C., Y.W.).
authors: Manoj
authors: M
authors: Rajadhyaksha
authors: Pfizer Inc., Groton, Connecticut (C.G., C.V., Ju.L., K.P., M.R., A.L.); and Pfizer Inc., Cambridge, Massachusetts (N.-P.N., Je.L., R.A.C., Y.W.).
authors: Jennifer
authors: J
authors: Liras
authors: Pfizer Inc., Groton, Connecticut (C.G., C.V., Ju.L., K.P., M.R., A.L.); and Pfizer Inc., Cambridge, Massachusetts (N.-P.N., Je.L., R.A.C., Y.W.).
authors: Alison
authors: A
authors: Logan
authors: Pfizer Inc., Groton, Connecticut (C.G., C.V., Ju.L., K.P., M.R., A.L.); and Pfizer Inc., Cambridge, Massachusetts (N.-P.N., Je.L., R.A.C., Y.W.).
authors: Roberto A
authors: RA
authors: Calle
authors: Pfizer Inc., Groton, Connecticut (C.G., C.V., Ju.L., K.P., M.R., A.L.); and Pfizer Inc., Cambridge, Massachusetts (N.-P.N., Je.L., R.A.C., Y.W.) yan.weng2@pfizer.com.
authors: Yan
authors: Y
authors: Weng
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics*; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D007074:Immunoglobulin G / Q000097:blood / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D007145:Immunoglobulin kappa-Chains / Q000097:blood / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D050505:Mutant Proteins / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000097:blood; D059748:Proteolysis; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015507:Drugs, Investigational; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007074:Immunoglobulin G; D007145:Immunoglobulin kappa-Chains; D050505:Mutant Proteins; C000604284:PF-05231023; D010446:Peptide Fragments; D011994:Recombinant Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors