Comparative evaluation of recommendations for preclinical studies of transporter-mediated drug–drug interactions

Abstract

Scientific relevance. Sound recommendations for preclinical studies of transporter- mediated pharmacokinetic interactions of medicinal products can help increase the likelihood of identifying potentially nephrotoxic and hepatotoxic medicinal products at the development and authorisation stages. However, overly strict requirements for the number of studies to be performed may lead to a significant increase in the cost of finished medicinal products.Aim. The aim was to compare regulatory documents on studying transporter-mediated drug–drug interactions (DDIs).Discussion. This review examines changes in regulatory requirements for studying DDIs in chronological order from the first guidelines that appeared in 1997. As exemplified in this article, the multiplicity of transporters and the lack of specific inhibitors pose significant challenges in assessing the role of a particular transporter in drug distribution and drug–drug interactions. This comparative review shows that extrapolating from in vitro transporter inhibition studies to in vivo pharmacokinetics can be misleading.Conclusions. A unified approach to studying transporter-mediated DDIs will increase the likelihood of identifying potentially toxic agents at the stage of new molecule screening. At the same time, it is advisable to limit the number of in vitro and in vivo transporter studies and recommend conducting these studies only for medicinal products with a narrow therapeutic index.

Keywords

• preclinical studies
• drug–drug interactions
• transporters
• pharmacokinetic models
• regulatory requirements