PT  - JOURNAL ARTICLE
AU  - Craig Giragossian
AU  - Chandra Vage
AU  - Jun Li
AU  - Kathleen Pelletier
AU  - Nicole Piché-Nicholas
AU  - Manoj Rajadhyaksha
AU  - Jennifer Liras
AU  - Alison Logan
AU  - Roberto A. Calle
AU  - Yan Weng
TI  - Mechanistic Investigation of the Preclinical Pharmacokinetics and Interspecies Scaling of PF-05231023, a Fibroblast Growth Factor 21–Antibody Protein Conjugate
AID  - 10.1124/dmd.114.061713
DP  - 2015 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 803--811
VI  - 43
IP  - 6
4099  - http://dmd.aspetjournals.org/content/43/6/803.short
4100  - http://dmd.aspetjournals.org/content/43/6/803.full
SO  - Drug Metab Dispos2015 Jun 01; 43
AB  - 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 IgG1κ 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.