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

Autor: Majtan T; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: tomas.majtan@ucdenver.edu., Bublil EM; Orphan Technologies Ltd., Rapperswill CH-8640, Switzerland., Park I; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA., Arning E; Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX 75226, USA., Bottiglieri T; Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX 75226, USA., Glavin F; Orphan Technologies Ltd., Rapperswill CH-8640, Switzerland., Kraus JP; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: jan.kraus@ucdenver.edu.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2018 May 01; Vol. 200, pp. 15-25. Date of Electronic Publication: 2018 Mar 09.
DOI: 10.1016/j.lfs.2018.03.018
Abstrakt: Aims: 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.
Main Methods: 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.
Key Findings: 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.
Significance: These results provide critical preclinical data for the design of first-in-human PEG-CBS clinical trial.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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