Journal Article

Pharmacokinetics (PK), Pharmacodynamics (PD) and Integrated PK/PD Modeling of a Novel Long Acting FGF21 Clinical Candidate PF-05231023 in Diet-Induced Obese and Leptin-Deficient Obese Mice

Yan, Qingyun, Bernardo, Barbara, Chabot, Jeffrey R., Zhu, Yimin, Vage, Chandra, Logan, Alison, Calle, Roberto, Talukdar, Saswata, Brenner, Martin B., Weng, Yan

2015

Overview

Pharmacological administration of fibroblast growth factor 21 (FGF21) improves metabolic profile in preclinical species and humans. FGF21 exerts its metabolic effects through formation of beta-klotho (KLB)/FGF receptor 1c FGFR1c complex and subsequent signaling. Data from various in vitro systems demonstrate the intact C- and N-terminus of FGF21 is required for binding with KLB, and interaction with FGFR1c, respectively. However the relative roles of the termini for in vivo pharmacological effects are unclear. Here we report PF-05231023, a long-acting FGF21 analogue which is unique in that the half-life and subcutaneous (s.c.) bioavailability of the intact C-terminus are significantly different from those of the intact N-terminus (2 vs. 22 hr for half-life and 4~7 vs. ~50% SC bioavailability). Therefore, this molecule serves as a valuable tool to evaluate the relative roles of intact C-terminus vs. N-terminus in in vivo pharmacology studies in preclinical species. We determined the effects of PF-05231023 administration on body weight (BW) loss and glucose reduction during an oral glucose tolerance test (OGTT) following SC and intravenous (i.v.) administration in diet-induced obese (DIO) and leptin-deficient obese (ob/ob) mice, respectively. Our data show that the intact N-terminus of FGF21 in PF-05231023 appears to be sufficient to drive glucose lowering during OGTT and sustain BW loss in DIOs. Further, PK/PD modeling suggests that while the intact FGF21 C-terminus is not strictly required for glucose lowering during OGTT in ob/ob mice or for BW reduction in DIO mice, the higher potency conferred by intact C-terminus contributes to a rapid initiation of pharmacodynamic effects immediately following dosing. These results provide additional insight into the strategy of developing stabilized versions of FGF21 analogs to harness the full spectrum of its metabolic benefits.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Administration, Intravenous / Analogs / Animal models / Animals / Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - pharmacokinetics / Antibodies, Monoclonal, Humanized - pharmacology / Antibodies, Monoclonal, Humanized - therapeutic use / Bioavailability / Blood Glucose - metabolism / Body weight / C-Terminus / Diabetes / Diet / Diet - adverse effects / Fibroblast growth factors / Fibroblast Growth Factors - administration & dosage / Fibroblast Growth Factors - pharmacokinetics / Fibroblast Growth Factors - pharmacology / Fibroblast Growth Factors - therapeutic use / Fibroblasts / Glucose / Glucose tolerance / Glucose Tolerance Test / Growth factors / Half-life / Homeostasis / In vivo methods and tests / Injections, Subcutaneous / Insulin resistance / Intravenous administration / Klotho protein / Leptin / Leptin - deficiency / Male / Metabolic disorders / Metabolites / Mice / Mice, Obese / Modelling / Models, Biological / N-Terminus / Obesity / Obesity - drug therapy / Pharmacodynamics / Pharmacokinetics / Pharmacology / R&D / Research & development / Rodents / Signaling / Time Factors / Weight control / Weight Loss - drug effects / Weight reduction