title: Translational Pharmacokinetic/Pharmacodynamic Analysis of MYO-029 Antibody for Muscular Dystrophy.
abstract: Suppression of the myostatin (GDF-8) pathway has emerged as an important therapeutic paradigm for muscle-wasting disorders. In this study, we conducted a translational pharmacokinetic/pharmacodynamic (PK/PD) analysis of MYO-029, an anti-myostatin monoclonal antibody, using PK data in mice, rats, monkeys, humans, mouse tissue distribution data with125I-labeled MYO-029, muscle weight increase in SCID mice, and muscle circumference changes in monkeys. This analysis revealed significant in vivo potency shift between mice and monkeys (72 nM vs. 1.3 μM for 50% effect on quadriceps). Estimated central clearance of MYO-029 (0.38 mL/h/kg) in humans was greater than twofold higher than typical IgG mAbs. Peak and trough steady-state exposures of MYO-029 in patients at biweekly intravenous doses of 10 mg/kg MYO-029 are predicted to achieve only 50% and 10% of the maximum effect seen in monkeys, respectively. These retrospective analyses results suggest that the MYO-029 exposures in this trial had a low probability of producing robust efficacy.
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer, Inc, Cambridge, Massachusetts, USA.
authors.forename: P
authors.initials: P
authors.lastname: Singh
authors.affiliation: Shire Pharmaceutical, Lexington, Massachusetts, USA.
authors.forename: H
authors.initials: H
authors.lastname: Rong
authors.affiliation: Nektar Therapeutics, Inc, San Francisco, California, USA.
authors.forename: T
authors.initials: T
authors.lastname: Gordi
authors.affiliation: Clermont Bosley LLC, Kennett Square, Pennsylvania, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bosley
authors.affiliation: Clinical Pharmacology, Pfizer, Inc, Cambridge, Massachusetts, USA.
authors.forename: I
authors.initials: I
authors.lastname: Bhattacharya
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D024510:Muscle Development / Q000187:drug effects; D009136:Muscular Dystrophies / Q000188:drug therapy* / Q000473:pathology; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects; D057170:Translational Research, Biomedical
chemical_list: D000906:Antibodies; C506829:Stamulumab