Evaluating the Pharmacodynamics and Protective Efficacy of Catalytic Bioscavenger following Subcutaneous Administration in Guinea Pigs
Abstract
Previous studies determined the guinea pig was a viableanimal model for evaluating subcutaneous (s.c.)injection as an alternative route of administration of catalytic Bioscavengers:enzymes designed to render nerve agents non‐toxic in systemic circulation following exposure. Recent studies have focused on evaluating the pharmacodynamics (PD) and protective efficacy (PE) of the lead bioscavenger candidate, organophosphorus hydrolase (OPH) variant, YT, as both unmodified and modified (PEGylated) versions of the enzyme. A comparative study was conducted with YT and three progressively sized PEG‐YT variants (934, 935, and 936) following a single bolus s.c. dose (5 mg/kg). Bioavailability increased linearly with molecular size such that the largest sized PEG‐YT variant, 936, afforded the highest bioavailability, thus promoting 936 to subsequent PD and PEstudies. Dose dependence on bioavailability was also examined via three cohorts of guinea pigs receiving doses (5, 15, 20 mg/kg) of either YT or 936 in which a linear dose response was also found. Guinea pigs receiving either YT or 936 (5 mg/kg) via intramuscular (i.m.)or s.c. routes had superimposable PD profiles regardless of route, suggesting an identical absorption pathway for the drugs. Protective efficacy was also evaluated by exposing the animals to 2xLD50 of sarin (GB) 7 dayspost‐enzyme administration; only the animals receiving 936 (i.m. and s.c.) survived 24 hours post‐exposure. Periodic s.c. dosing strategies were also evaluated with 936 in which three injections were administered either 2 or 24 hours apart for a total dose of 15 mg/kg followed by a protective efficacy assessment 8 days post‐administration. Overall these data support the use of s.c. injection as a practical route of administration for catalytic bioscavenger with PE Gylation, synergistically enhancing both bioavailability and extending drug half‐life in circulation.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2018
- Source ID
- 10.1096/fasebj.2018.32.1_supplement.lb90
Entities
People
- Douglas Cerasoli
- Michael Boeri
- Sandra J DeBus
- Shane Kasten
- Thuy Dao
- Zachary Canter
Organizations
- Oak Ridge Institute for Science and Education
- United States Army Medical Research Institute of Chemical Defense
- United States Department of Energy