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Pharmacokinetics and pharmacodynamics of PEGylated truncated human cystathionine beta-synthase for treatment of homocystinuria

Majtan, Tomas, Bublil, Erez M., Park, Insun, Arning, Erland, Bottiglieri, Teodoro, Glavin, Frank, Kraus, Jan P.
Life sciences 2018 v.200 pp. 15-25
allometry, blood, clinical trials, cystathionine beta-synthase, dose response, half life, homocysteine, homocystinuria, humans, inflammation, macrophages, metabolites, mice, models, monkeys, pharmacodynamics, pharmacokinetics, rats, therapeutics, tissues, toxicity
PEGylated human truncated cystathionine beta-synthase, lacking the C-terminal regulatory domain (PEG-CBS), is a promising preclinical candidate for enzyme replacement therapy in homocystinuria (HCU). It was designed to function as a metabolic sink to decrease the severely elevated plasma and tissue homocysteine concentrations. In this communication, we evaluated pharmacokinetics (PK), pharmacodynamics (PD) and sub-chronic toxicity of PEG-CBS in homocystinuric mice, wild type rats and monkeys to estimate the minimum human efficacious dose for clinical trials.Animal models received single or multiple doses of PEG-CBS. Activity of PEG-CBS and sulfur amino acid metabolites were determined in plasma and used to determine PK and PD.The plasma half-lives of PEG-CBS after a single subcutaneous (SC) injection were approximately 20, 44 and 73 h in mouse, rat and monkey, respectively. The SC administration of PEG-CBS resulted in a significant improvement or full correction of metabolic imbalance in both blood and tissues of homocystinuric mice. The PD of PEG-CBS in mouse was dose-dependent, but less than dose-proportional, with the maximal efficacy achieved at 8 mg/kg. PEG-CBS was well-tolerated in mice and monkeys, but resulted in dose-dependent minimal-to-moderate inflammation at the injection sites and vacuolated macrophages in rats. Allometric scaling of animal data was linear and the estimated human efficacious dose was determined as 0.66 mg/kg administered once a week.These results provide critical preclinical data for the design of first-in-human PEG-CBS clinical trial.