Implications and consequences of enzyme induction on preclinical and clinical drug development

1. Enzyme induction has traditionally been studied during drug development to assess the potential of drug entities to interact with concomitant medic ations and alter their pharmacological effects, and clearly it is an unwant ed phenomenon. However, another hurdle caused by induction occurs during pr eclinical development via the attainment of safety data, obtained by dosing high quantities of compound to species used in toxicology assessment. This review considers the techniques that can now be utilized in drug discovery , their relevance, the pharmacokinetic aspects of this phenomenon, and it d iscusses the consequences and implications of induction during preclinical and clinical development. 2. It is becoming increasingly routine to employ hepatocyte cultures and no vel techniques such as quantitative real-time reverse transcriptase PCR to identify enzyme inducers in vitro. The major challenge is to utilize these in vitro data to predict the consequences of induction in vivo. From an und erstanding of pharmacokinetic principles and low clinical doses relative to preclinical studies, there is limited potential for induction by a develop ment candidate to significantly alter the pharmacological efficacy of a coa dministered drug. 3. The most comprehensive approach when considering induction involves inte grating quantitative in vitro data, information on the pharmacokinetic beha viour of the compound and the PK/PD relationship in order to predict its co nsequences. The generation of this holistic strategy would enable more deta iled and informed decisionmaking about both the suitability of molecules fo r development and the development strategy itself.