Translational Human Health Assessment of Carfentanil Using an Experimentally Refined PBPK Model
Abstract
Methods for measuring acute toxicity and risk assessments for acutely toxic materials require large numbers of animal subjects, multiple species, specialized infrastructure, and personnel training. This study demonstrated that carfentanil toxicity can be accurately modeled using a physiologically based pharmacokinetic (PBPK) model refined with in vitro and ex vivo experimental data and a limited in vivo animal study. Experiments were performed to measure plasma protein binding, blood partitioning, and microsomal clearance in rabbit and human plasma, whole blood, and liver microsomes, respectively. Rabbit properties were incorporated into a rabbit physiology within the PBPK model, and kinetics were compared with those of a small cohort of rabbits exposed intravenously to carfentanil. The properties refined the predicted kinetics to reflect those seen in vivo as a validation of the PBPK model. Upon successful validation in the rabbit physiology, the model was changed to human physiology, populated with human data, and optimized for dose-equivalence. The equivalent human dose to a loss of righting reflex endpoint as indicated by the rabbit surrogate was 0.34 g/kg. This confirms that carfentanil is an acutely toxic material and provides, for the first time, a human toxic dose without a need for forensic toxicology or non-physiological extrapolation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2018
- Accession Number
- AD1060142
Entities
People
- Ariane Wohlfarth
- Marilyn A. Huestis
- Michael G Feasel
- Richard J. Lawrence
- Robert L. Kristovich
Organizations
- Edgewood Chemical Biological Center
- National Institute on Drug Abuse