title: 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.
abstract: 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.
authors: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Research Unit, Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts, 02139, United States of America; Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts, 02139, United States of America.
authors: Yan
authors: Y
authors: Weng
authors: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Research Unit, Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts, 02139, United States of America; Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts, 02139, United States of America.
authors: Jeffrey R
authors: JR
authors: Chabot
authors: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Research Unit, Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts, 02139, United States of America.
authors: Barbara
authors: B
authors: Bernardo
authors: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Research Unit, Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts, 02139, United States of America.
authors: Qingyun
authors: Q
authors: Yan
authors: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Research Unit, Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts, 02139, United States of America.
authors: Yimin
authors: Y
authors: Zhu
authors: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Research Unit, Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts, 02139, United States of America.
authors: Martin B
authors: MB
authors: Brenner
authors: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts, 02139, United States of America.
authors: Chandra
authors: C
authors: Vage
authors: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Research Unit, Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts, 02139, United States of America.
authors: Alison
authors: A
authors: Logan
authors: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Research Unit, Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts, 02139, United States of America.
authors: Roberto
authors: R
authors: Calle
authors: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Research Unit, Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, Massachusetts, 02139, United States of America.
authors: Saswata
authors: S
authors: Talukdar
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D005951:Glucose Tolerance Test; D007279:Injections, Subcutaneous; D020738:Leptin / Q000172:deficiency*; D008297:Male; D008820:Mice, Obese; D008954:Models, Biological; D009765:Obesity / Q000188:drug therapy*; D013997:Time Factors; D015431:Weight Loss / Q000187:drug effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D001786:Blood Glucose; D020738:Leptin; C000604284:PF-05231023; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors