Development of an in vitro system and model-based translational framework to assess haemolysis risk following intravenous abuse of medications containing polyethylene oxide

Autor: Eric Galia, Gerwin E. Engels, Peter Persich, Susanne Thun, Stéphan Benay, Willem van Oeveren
Rok vydání: 2020
Předmět:
Zdroj: Toxicology in Vitro. 65:104776
ISSN: 0887-2333
DOI: 10.1016/j.tiv.2020.104776
Popis: Multiple cases of potentially life-threatening thrombotic microangiopathy (TMA) have resulted from intravenous abuse of medications containing polyethylene oxide (PEO), most often Opana ER (oxymorphone hydrochloride extended release). No validated models are available to assess the risk of TMA with different formulations and extraction methods following intravenous abuse. We have developed an in vitro system that involves passing pooled blood containing the excipient of interest through a syringe needle and assessing haemolysis via haemoglobin release. Haemolysis is induced by high shear stress caused by the flow of blood containing PEO through a narrow-bore syringe needle, recapitulating the mechanism in small blood vessels. Using the in vitro system, we demonstrate that high-molecular-weight PEO (>1 MDa) induces haemolysis in a concentration-dependent manner under flowing but not static conditions. We use data from the in vitro system and published in vivo data to predict the time course of the haemolytic response in vivo via a pharmacometric model. The in vitro system is a novel method for investigating factors influencing PEO-induced haemolysis. In combination with our model-based translational framework, the in vitro system allows straightforward assessment of the haemolytic potential of PEO-containing medications, and may find application in gauging TMA risk following intravenous abuse.
Databáze: OpenAIRE
Externí odkaz: