On the development of physiologically based toxicokinetic models (PBTK) for cardiovascular implants

Regul Toxicol Pharmacol. 2023 Aug 31:105489. doi: 10.1016/j.yrtph.2023.105489. Online ahead of print.ABSTRACTLocal and systemic contamination caused by metal ions leaching from medical device materials is a significant and continuing health problem. The increasing need for verification and validation, and the imposition of stringent government regulations to ensure that the products comply with the quality, safety, and performance standards, have led regulatory bodies worldwide to strongly recommend the use of modeling and simulation tools to support medical device submissions. A previously published physiologically-based toxicokinetic (PBTK) model, is here expanded and enriched by an additional separate tissue compartment to better resemble normal physiology and by the introduction of time-dependent functions to describe all biokinetic parameters. The new model is exercised in conjunction with state-of-the-art probabilistic, Monte Carlo methodology to calculate the prediction's confidence intervals and incorporate variability associated with toxicological biodistribution studies. The quantitative consistency of the model-derived predictions is validated against reported data following the implantation of nickel-containing cardiovascular devices in humans and minipigs. Finally, a new methodology for compartmental toxicological risk assessment is presented that can be used for forward or reverse dosimetry. Our work is aimed at providing a computational tool to optimize the dev...
Source: Regulatory Toxicology and Pharmacology : RTP - Category: Toxicology Authors: Source Type: research