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.

KEYWORDS:

• ADME
• clinical pharmacokinetics
• co-medication
• drug-drug interactions
• drug transporters
• in vitro methodology
• perpetrator
• prediction
• statins
• victim

Article highlights

• The prevalence of DDI is increasing due to ageing populations and the associated practice of polypharmacy as a result of co-morbidities; 50% of patients over the age of 65 years are reportedly prescribed ≥5 drugs.

• From a transporter DDI risk perspective, the potential to inhibit transporters is of the greatest concern during development of investigational drugs due to the safety impact of increased exposure of some common co-medications and the adverse effect it may present to recruiting patients to clinical trials.

• Knowledge of co-medication prescription rates for a disease indication will aid the identification of critical co-medications.

• Understanding the clinically relevant disposition pathways of critical co-medications determines what transporters to focus on (and when) for evaluating DDI perpetrator potential of investigational drugs during discovery and development.

• It is vital that all in vitro transporter IC₅₀ determinations be conducted with the inclusion of a pre-incubation step with investigational drug, regardless of transporter, in order to remove any artefactual underestimation of the IC₅₀ (K_i) parameter, thereby ensuring the correct IC₅₀ value is obtained for accurate DDI risk assessment.

• The degree that active transport contributes to a transporter disposition pathway (defined by f_e value) dictates the maximal theoretical exposure (AUCR) change possible in DDI.

• Use of transporter f_e values with mechanistic static equations accurately predicts the observed AUCRs of 28 clinically significant DDIs involving six different statin victim drugs with a range of perpetrator drugs.

This box summarizes key points contained in the article.

Declaration of interest

R Elsby, H Atkinson and P Butler are employees of Cyprotex Discovery Ltd (an Evotec company). RJ Riley is an employee of Evotec. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.