Studying the right transporter at the right time: an in vitro strategy for assessing drug-drug interaction risk during drug discovery and development

Abstract

Introduction: Transporters are significant in dictating drug pharmacokinetics, thus inhibition of transporter function can alter drug concentrations resulting in drug-drug interactions (DDIs). Because they can impact drug toxicity, transporter DDIs are a regulatory concern for which prediction of clinical effect from in vitro data is critical to understanding risk. Area covered: The authors propose in vitro strategies to assist mitigating/removing transporter DDI risk during development by frontloading specific studies, or managing patient risk in the clinic. An overview of clinically relevant drug transporters and observed DDIs is provided, alongside presentation of key considerations/recommendations for in vitro study design evaluating drugs as inhibitors or substrates. Guidance on identifying critical co-medications, clinically relevant disposition pathways, and using mechanistic static equations for quantitative prediction of DDI is compiled. Expert opinion: The strategies provided will facilitate project teams to study the right transporter at the right time to minimize development risks associated with DDIs. To truly alleviate or manage clinical risk, the industry will benefit from moving away from current qualitative basic static equation approaches to transporter DDI hazard assessment towards adopting the use of mechanistic models to enable quantitative DDI prediction, thereby contextualizing risk to ascertain whether a transporter DDI is simply pharmacokinetic or clinically significant requiring intervention.