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ICCVAM Biennial Report 2018-2019

Biennial Progress Report 2018-2019 Interagency Coordinating Committee on the Validation of Alternative Methods

Use of a PBPK Model to Derive a Human-equivalent Dose

CCDC CBC has successfully used physiologically based PK modeling to derive a high-fidelity human-equivalent dose of the ultra-potent opioid carfentanil. This effort included validating the pharmacokinetics of carfentanil in an in vivo rabbit model with the rabbit PBPK in silico model, converting to a human physiology of interest, and then calculating an equivalent dose by optimizing the maximal plasma concentration and area under the curve of the PK profile. CCDC CBC’s predicted human-equivalent lethal dose of carfentanil differed from that of the U.S. Drug Enforcement Administration by only 50 ng. CCDC CBC’s PK profile is also supported by a Canadian report of an overdose of carfentanil by inhalation administration in which periodic blood samples were analyzed for carfentanil concentration from admission into the emergency department until discharge.

Current efforts aim to convert this intravenous human equivalent dose into an inhaled dose by using the PBPK model’s pulmonary administration module. Additionally, CCDC CBC aims to predict dermal absorption in a reliable way using the transdermal module of their PBPK software suite.