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 IgG 1k 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.

FGF21 Regulates Sweet and Alcohol Preference

“…To determine whether FGF21 also affects sweet preference in primates, we analyzed saccharin preference in obese cynomolgus monkeys administered PF-05231023, a long-acting FGF21 analog consisting of two molecules of modified FGF21 linked by an antibody scaffold (Dong et al, 2015; Giragossian et al, 2015; Weng et al, 2015). We first tested this analog in mice.…”

Pharmacokinetics and pharmacodynamics of PF‐05231023, a novel long‐acting FGF21 mimetic, in a first‐in‐human study

“…PF‐05231023 was administered to subjects with T2DM as a single dose of 0.5 mg or 1.5 mg IV bolus or 5, 15, 50, 100 or 200 mg 1‐h IV infusion on Day 1. The starting dose of 0.5 mg was predicted based on the PK properties in rats and nonhuman primates, and allometric scaling as described previously to generate exposures similar to human endogenous FGF21 plasma levels and thus not expected to elicit pharmacological activity. Using the PK/PD model previously developed for PF‐05231023, coupled with projected human PK parameters, IV administration of PF‐05231023 to humans in the range 5–10 mg was projected to deliver intact C‐terminus and intact N‐terminus exposures that elicited glucose lowering as observed in ob/ob mice .…”

“…Therefore, plasma levels of both intact C‐terminus and intact N‐terminus of PF‐05231023 were assessed in the present study. PK studies were conducted in rats and nonhuman primates in order to predict the PK of PF‐05231023 in humans, identify safe exposure margins using the no observed adverse effect level (NOAEL) in toxicology studies, and support dose selections for the FIH study .…”

Proteolysis and Oxidation of Therapeutic Proteins After Intradermal or Subcutaneous Administration

“…Various literature values of the thoracic lymph duct flow rates were mentioned by Giragossian et al 114 Length of the thoracic lymph duct 7). These data was originally reported by Jain et al 97 (Reproduced with permission).…”