Importance of In Vitro Tools in Drug Interaction Studies

Drug interactions can be defined as the modification of the safety and efficacy profile of a medication following the coadministration of drugs, environmental pollutants, ingredients or additives present in the diet (see 5.35 Modeling and Simulation of Pharmacokinetic Aspects of Cytochrome P450-Based Metabolic Drug-Drug Interactions).

Drug interactions are usually defined as being either of pharmacodynamic or of pharmacokinetic origin. These two aspects are closely linked and need to be studied together to evaluate both safety and efficacy in the clinic. Only the latter category, defined also as metabolism-based interactions (i.e., the alteration of the metabolic clearance of a drug by another coadministered drug) will be further detailed in this chapter.

With the increasing prevalence of polypharmacy,51'52 these drug interactions have become more frequent,51'53'54 and can lead to serious side effects, e.g., Cerivastatin55 and increased morbidity and mortality.54

It is well recognized that testing in the clinic all the possible combinations between an NCE and the potential interacting compounds on the market is impossible for obvious cost and time reasons, but also because it is nonrelevant. In vitro studies have therefore become essential to explore the molecular mechanisms involved in these drug interaction processes with the aim of first selecting a compound with a safe or a controlled drug interaction profile but also in order to help in the future design and optimization of drug interaction clinical studies.

In 2003, the Pharmaceutical Research and Manufactures of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical working Groups have defined a minimal in vitro and in vivo pharmacokinetic drug interaction package for registration purposes.46 In October 2004, a preliminary concept paper of the US Food and Drug Administration (FDA) has focused more on study design, data analysis, as well as implications on dosing and labeling.45 CYP are involved in the metabolism of more than 90% of currently available drugs56 and are recognized by regulatory authorities as an important cause of drug interactions.57,58 Therefore, the guidelines focus essentially on those enzymes that can be inhibited, activated, or induced by concomitant drug treatments. These changes in enzyme activities may significantly increase or decrease the exposure of the body to the drug or metabolites at potentially toxic levels. The approaches described can however be adapted to other enzymes.

This chapter suggests the following general topics to be investigated during the drug development program:

• Drug metabolism enzyme identification

• Evaluation of CYP inhibition

• Evaluation of CYP induction.

A pragmatic approach is recommended to define the drug interaction strategy which will, at the registration level, be able to justify the selection of the interacting compounds used during the clinical trials, limit the number of clinical studies to be undertaken, and, finally, in the labeling, position the compound as regards future comedications as well as suggest dosage adjustments if required.46

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