Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Regulatory Considerations on Drug Interaction Studies ***

Stephan Becker (Abschlußjahr: 2009)

Language: Englisch

Nowadays drug interaction studies are an important part of the drug development process. The pharmacodynamic effects of a drug are generally related to its concentrations at its side of action. Therefore changes in drug absorption, distribution metabolism and excretion may lead to altered drug levels resulting in toxic reactions or reduced effectiveness. These steps may be affected by co-administration of drugs and might lead to serious adverse events.

In the past no specific recommendations on the investigation of drug interactions were part of the drug approval process. Unexpected drug interactions were primarily described as case reports in the medical literature and a profound mechanistic understanding of drug interactions was missing. In the following years increasing numbers of reports on serious adverse events were associated with drug interactions. In parallel the scientific knowledge of drug interactions and drug interaction studies has improved. Several in-vitro techniques have been developed from the 1980s until now (especially for drug metabolising CYP enzymes) which have allowed investigation of these interactions. EMEA and FDA published in 1997 and 1999 guidelines dealing with drug interaction studies. Since these guidelines were published further scientific advantages in the field of in-vitro and in-vivo drug interaction studies have been made (e. g. inclusion of drug transporters). It was recognised that the current guidelines did not fully reflect the scientific knowledge of the present time.

This thesis describes the pharmacological background of drug interactions, possible interacting pathways and the consequences which may arise from them. Furthermore methods and experimental procedures which can be used to evaluate drug interactions in-vitro and in-vivo are illustrated, based on the requirements set out by relevant guidelines and scientific publications.
The regulatory agencies encourage pharmaceutical companies to perform drug interaction studies at early stages of the drug development process, since meaningful results may significantly influence the design of further in-vivo drug interaction studies. In-vitro studies may reduce the need for in-vivo studies, since unaffected interacting pathways can be excluded. An integrated approach between in-vitro and in-vivo studies should help to get a better insight into the respective drug interaction mechanisms.
Nevertheless drug interaction studies are still a field under scientific development, therefore respective guidelines have to be updated regularly in the future. The FDA has recently published a draft guidance document which includes the scientific progress made in the last years. The document includes descriptions of experimental settings, guidance for decision making, enhancements in the field of CYP-based interaction studies and the inclusion of transporter-based interactions as a part of drug development process. Also, the EMEA has recently published a concept paper on the need for revision of the drug interaction guideline. Interested parties are invited to contribute in the update process of the former guidance document.
The information on drug interactions obtained in the course of drug development process has to be presented in the SPC and PIL in a way which allows health care professionals to apply drugs properly. It should be clearly stated which interactions are clinical relevant and which may lead to serious drug interactions. This may result in contraindications of certain drug combinations. Dosage adjustments for drug combinations should also be mentioned in the SPC as well as lacks of interactions.

A profound knowledge on drug interactions may help to reduce the risks of serious adverse events. The integration of drug interaction studies is an integral part in drug development process and may help to individualise drug dosing in the sense of an optimised drug therapy and to reduce the risk of interaction-based adverse drug reactions.

Pages: 63, annexes: 4 pages