Regulatory Focus™ > News Articles > European Regulators Issue 'Major Revision' to Guideline on Investigating Drug Interactions

European Regulators Issue 'Major Revision' to Guideline on Investigating Drug Interactions

Posted 09 July 2012 | By Alexander Gaffney, RAC 

The European Medicines Agency (EMA) on Friday, 6 June issued an updated guideline on the investigation of drug-drug interactions, giving the guidance its first "major revision" since 1998.

The guidance addresses the "potential for pharmacokinetic interactions between new medicinal products and already marketed drugs" and other products-including food-and how to best address drug-drug interactions (DDI) through in vitro and in vivo studies. DDIs are commonly associated with adverse events, and EMA said they are a common cause of hospital admissions and patient deaths.

EMA regulators said the updated document "outlines a comprehensive, systematic and mechanistic approach to the evaluation of the interaction potential of a drug during its development and offers guidance to ensure that the prescriber receives clear information on the interaction potential as well as practical recommendations on how the interactions should be managed during clinical use."

"Today's update brings the guideline in line with scientific advances in the investigation of drug interactions," EMA explained. "These include the ability to predict clinically relevant drug interactions from a limited number of well-designed studies, as well as progress in understanding of enzyme induction and drug-transporter interactions in recent years."

The Guideline

Sponsors of drug applications should assess pharmacodynamic interactions between drugs "which compete with each other" at the target site and if "drug are likely to be used concomitantly."

Pharmacokinetic interactions should be assessed using in vitro and in vivo studies, and EMA notes animal studies will usually not be relevant "due to the marked species differences," making the extrapolation of collected data "difficult." ADME studies-absorption, distribution, metabolism and excretion-should also be conducted, and EMA's guideline provides extensive instruction about which factors to consider when conducting such tests.

EMA also notes DDI studies should usually be conducted in healthy adults unless it is necessary to include patients for tolerability or safety reasons. These studies should be performed using validated probe drugs, which are drugs metabolism by one specific enzyme or transporter, which should allow for the effect of the second drug to be easily noted. These so-called "cocktail studies" involving probe drugs are also extensively covered in the guideline, and EMA provides a list of accepted probe drugs in an attached appendix.

"The clinical relevance of the effects of the studied drugs on the pharmacokinetics of the investigational drug should be assessed and the results used to predict the effects of other drugs where a similar interaction by the same mechanism can be expected," EMA writes in its guideline. "Treatment recommendations should ensure that patients receive drug treatment which is effective and safe."

The updated guideline comes into effect 1 January 2013.

Read more:

EMA - Guideline on the Investigation of Drug Interactions

EMA - European Medicines Agency updates guideline on drug interactions

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