2018 Majtan 20NHS PEG-CBS PK PD mouse rat monkey allometry.pdf (1.57 MB)

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

Download (1.57 MB)
journal contribution
posted on 08.03.2019 by Tomas Majtan, Erez M. Bublil, Insun Park, Erland Arning, Teodoro Bottiglieri, Frank Glavin, Jan P. Kraus
Aims: PEGylated human truncated cystathionine beta-synthase, lacking the C-terminal regulatory domain (PEGCBS),
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 subchronic
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-tomoderate
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
Significance: These results provide critical preclinical data for the design of first-in-human PEG-CBS clinical trial.


Grant ID