Clinical drug-drug interaction studies: methods, pitfalls and interpretation

From the EACPT Focus Meeting on How to Assess Medicines, Opatija, 6-9 October 2016. In this video, Donald Singer discusses with Janne Backman from Helsinki how to identify and minimise risk of drug-drug interactions.

Discussants
Janne Tapio Backman: Professor in Clinical Pharmacology and Individual Medicine, University of Helsinki, Finland
Professor Donald Singer: member of the Executive Committee of the EACPT and member  of the European Medicines Agency Health Professionals Working Party.

Here is a summary of the key points from Professor Backman's  talk at the EACPT Focus Meeting in Opatija: 

Drug-drug interactions can either markedly reduce or enhance the therapeutic or adverse effects of drugs by causing alterations in the pharmacokinetics or pharmacodynamics of drugs. If such interactions are not understood or accounted for in patient care, they can have harmful, even hazardous clinical consequences. 

Drug-drug interactions have been a major cause of drug withdrawals from the market. Regulatory agencies, including the European Medicines Agency (EMA) have therefore published guidance documents that are designed for the industry to guide their DDI studies during drug development. In particular, detailed scientific recommendations can be given concerning pharmacokinetic interactions, because such interactions can be mediated via mechanistic changes in absorption, distribution, metabolism and excretion of drugs. 

Specific approaches are suggested concerning cytochrome P450 enzymes (CYPs), non-CYP enzymes and membrane transporters. In addition, current guidance also recommends use of modelling approaches, such as physiologically based pharmacokinetic (PBPK) models to design and extend the interpretation of preclinical and clinical drug-drug interaction studies. For designing clinical drug-drug interactions studies, detailed preclinical in vitro and early clinical pharmacokinetic information is necessary. 

Despite detailed guidelines, there are many challenges in characterization of the interaction potential of a drug, both as a perpetrator and as a victim of the interaction. Such challenges arise from complex interaction mechanisms, eg, simultaneous involvement of transporters and drug metabolizing enzymes, autoinhibition and autoinduction of metabolism, time-dependent inhibition and involvement of major drug metabolites. 

Understanding the challenges and pitfalls of drug-drug interaction studies is thus necessary in interpretation of the results of studies. In this lecture, basic methods of clinical drug-drug interaction studies will be reviewed, with examples of potential pitfalls and basic principles of interpretation.
  
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