Interspecies scaling in pharmacokinetics: a novel whole-body physiologically based modeling framework to discover drug biodistribution mechanisms in vivo

Abstract

Drug approval processes require extensive testing and have recently put more emphasis on understanding mechanistic drug action in the body including toxicity and safety.1 Consequently, there is an urgent need in the pharmaceutical industry to develop mechanistic pharmacokinetic (PK) models able to both expedite knowledge gain from experimental trials and, simultaneously, address safety concerns. We previously developed a first principles based whole-body PK model, which incorporated physiological dimensions and drug mass transport. In this follow-up article, we demonstrate how the first principles model in combination with novel physiological scaling laws yields more reliable interspecies and intraspecies extrapolation of drug biodistribution. We show how experimental dose-response data in rats for immunosuppressant cyclosporin are sufficient for predicting the biodistribution of this drug in pigs, monkeys, and humans. The predicted drug concentrations extrapolated by interspecies scaling laws match well with the experimental measurements. These promising results demonstrate that the whole-body PK modeling approach not only elucidates drug mechanisms from a biochemical standpoint, but offers better scaling precision. Better models can substantially accelerate the introduction of drug leads to clinical trials and eventually to the market by offering more understanding of the drug mechanisms, aiding in therapy design, and serving as an accurate dosing tool.