Drug-drug interactions of new active substances: mibefradil example

Mibefradil was approved as a novel calcium antagonist in Switzerland in 1996. Following its launch as an antihypertensive and anti-anginal agent, there were reports about serious pharmacokinetic and pharmacodynamic interactions occurring with other drugs frequently administered to patients with cardiovascular diseases. Despite appropriate modifications of the prescribing information, such interactions continued to occur. The drug was finally withdrawn after a study in patients with congestive heart failure showed a trend to higher mortality with mibefradil. This increase in mortality could again be due to multiple interactions between mibefradil and other drugs. In retrospect, it can be concluded that several of the interactions, including the theoretical risk of severe toxicity in some patients, could have been and in fact were predicted on the basis of the data available before introduction to the market. Depending on the benefits, these problems would however not necessarily represent an unacceptable risk for a new active compound.

The most important points revealed by this analysis were: (1) when interpreting the results of interaction studies, it is important to consider not only the mean of the interaction effect but also the observed and the theoretically conceivable extreme effects in individual subjects and (2) a drug with a high interaction potential may represent a high risk even if an adequate warning is included in the product information. The need for specific pharmacokinetic and pharmacodynamic interaction studies with new drugs and the limitations of the pivotal clinical efficacy and safety studies during phase III in order to reveal such interactions are discussed.