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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 with ¹²⁵ I-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 ?M 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.

SUBMITTER: Singh P

PROVIDER: S-EPMC5351001 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Translational Pharmacokinetic/Pharmacodynamic Analysis of MYO-029 Antibody for Muscular Dystrophy.

Singh P P Rong H H Gordi T T Bosley J J Bhattacharya I I

Clinical and translational science 20161004 6

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 with <sup>125</sup> I-labeled MYO-029, muscle weight increase in SCID mice, and muscle circumference changes in monkeys. This analysis revealed significant ...[more]

PMID: 27700008

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Project description:Canakinumab is a high-affinity human monoclonal anti-interleukin-1? (IL-1?) antibody of the IgG1/? isotype designed to bind and neutralize the activity of human IL-1?, a pro-inflammatory cytokine. Canakinumab is currently being investigated on the premise that it would exert anti-inflammatory effects on a broad spectrum of diseases, driven by IL-1?. This paper focuses on the analysis of the pharmacokinetic and pharmacodynamic data from the canakinumab clinical development programme, describing results from the recently approved indication for the treatment of cryopyrin-associated periodic syndromes (CAPS) under the trade name ILARIS®, as well as diseases such as rheumatoid arthritis, asthma and psoriasis. Canakinumab displays pharmacokinetic properties typical of an IgG1 antibody. In a CAPS patient weighing 70?kg, slow serum clearance (0.174?L/day) was observed with a low total volume of distribution at steady state (6.0?L), resulting in a long elimination half-life of 26 days. The subcutaneous absolute bioavailability was high (70%). Canakinumab displays linear pharmacokinetics, with a dose-proportional increase in exposure and no evidence of accelerated clearance or time-dependent changes in pharmacokinetics following repeated administration was observed. The pharmacokinetics of canakinumab in various diseases (e.g. CAPS, rheumatoid arthritis, psoriasis or asthma) are comparable to those in healthy individuals. No sex- or age-related pharmacokinetic differences were observed after correction for body weight. An increase in total IL-1? was observed in both healthy subjects and all patient populations following canakinumab dosing, reflecting the ability of canakinumab to bind circulating IL-1?. The kinetics of total IL-1? along with the pharmacokinetics of canakinumab were characterized by a population-based pharmacokinetic-binding model, where the apparent in vivo dissociation constant, signifying binding affinity of canakinumab to circulating IL-1?, was estimated at 1.07?±?0.173?nmol/L in CAPS patients. During development of canakinumab a cell line change was introduced. Pharmacokinetic characterization was performed in both animals and humans to assure that this manufacturing change did not affect the pharmacokinetic/pharmacodynamic properties of canakinumab.

Dataset Information

Translational Pharmacokinetic/Pharmacodynamic Analysis of MYO-029 Antibody for Muscular Dystrophy.

Publications

Translational Pharmacokinetic/Pharmacodynamic Analysis of MYO-029 Antibody for Muscular Dystrophy.

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