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 medications and alter their pharmacological effects, and clearly it is an unwanted phenomenon. However, another hurdle caused by induction occurs during preclinical 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 discusses the consequences and implications of induction during preclinical and clinical development. 2. It is becoming increasingly routine to employ hepatocyte cultures and novel 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 understanding of pharmacokinetic principles and low clinical doses relative to preclinical studies, there is limited potential for induction by a development candidate to significantly alter the pharmacological efficacy of a co-administered drug. 3. The most comprehensive approach when considering induction involves integrating quantitative in vitro data, information on the pharmacokinetic behaviour of the compound and the PK/PD) relationship in order to predict its consequences. The generation of this holistic strategy would enable more detailed and informed decision-making about both the suitability of molecules for development and the development strategy itself.
Worboys
P D
PD
Merck Sharp & Dohme, Neuroscience Research Centre, Harlow, UK.
Carlile
D J
DJ
D000818:Animals; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D010599:Pharmacokinetics; D014116:Toxicology