European Guidance on the Investigation of Drug Interactions

The European Agency for the Evaluation of Medicinal Products issued in December 1997 a note for guidance on the investigation of drug interactions [98]. This guidance took effect in June 1998. Unlike the FDA guidance which only dealt with the in vivo metabolic aspects of drug interactions, the European guidance covered both pharmacodynamic and pharmacokinetic drug interactions (absorption, distribution, and elimination both at the renal excretion and hepatic/biliary levels as well as changes in blood flow).

The European guidance makes certain recommendations that are either not covered or sligthly differ from the FDA recommendations. These recommendations are as follows:

A. The need for a pharmacodynamic interaction study should be determined on a case by case basis taking into account the following points:

1. When the drugs likely to be co-administered have similar mechanisms of action or potentially similar interaction mechanisms.

2. When drugs likely to be co-administered have similar or opposing pharmacodynamic effects.

B. In vitro studies may be helpful in investigating the transport mechanism and whether a drug is a substrate or an inhibitor of P-glycoprotein. However, the guidance recommends that potential interactions at this level be confirmed by well-designed in vivo studies since current in vitro studies have shown to be of limited value in predicting the magnitude of the interaction.

C. Displacement interaction studies should be performed when the investigated drug:

- Has nonlinear protein binding.

- The volume of distribution is small.

- Has a narrow therapeutic index.

- Is highly bound (>95%) to plasma proteins at therapeutic concentrations.

- Occupies most of the binding sites (such as when the plasma therapeutic concentrations at the highest recommended dose exceed the plasma binding capacity).

- When the investigated drug is administered intravenously and possesses a high metabolic extraction ratio.

- Displacement studies should probably be done in vivo, since the metabolites may also be involved in the interaction. If the studies are performed in vitro, then the possible contribution of the metabolites should also be considered.

D. In general, the guidance recommends conducting an in vitro or in vivo metabolic interaction studies for metabolic pathways responsible for 30% or more of the total clearance. However, if toxic/active metabolites are formed by minor metabolic pathways, the effect of co-administered inhibitors or inducers of these pathways should also be investigated.

E. Subjects participating in metabolic in vivo interaction studies should be appropriately genotyped and/or phenotyped if any of the active enzymes mediating the metabolism are polymorphically distributed in the population.

F. For inducers or inhibitors, steady-state conditions should be achieved whenever possible. Approved therapeutic dose regimens should be used in these studies.

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