Clinical-pharmacological strategies to assess drug interaction potential during drug development

Drug interactions in patients receiving multiple drug regimens are a constant concern for the clinician. With the increased availability of new drugs and their concomitant use with other drugs, there has been a rise in the potential for adverse drug interactions as demonstrated by the recent withdrawals of newly marketed drugs because of unacceptable interaction profiles. Therefore, the interaction potential of a new compound has to be assessed in detail, starting with preclinical in vitro and in vivo studies at candidate selection and continuously followed up through preclinical and clinical development. Since formal in vivo studies of all possible drug interactions are neither practicable nor suggestive, a careful selection of a limited number of drug combinations to be investigated in vivo during the development phase is indicated. Based on knowledge of pharmacokinetic and biopharmaceutical properties, a well balanced link between in vitro investigations and carefully selected in vivo interaction studies allows full assessment of the potential of a new drug to cause clinically relevant pharmacokinetic drug-drug interactions, prediction of a lack of interactions and derivation of the proper dose recommendations. Clinical pharmacology plays a number of key roles within the process of collecting information on drug interactions during preclinical and clinical development: addressing issues and/or favourable properties to be expected, thus contributing to the scientific assessment of development potential; setting up a rational in vivo drug-drug interaction programme; performing early mechanistic studies to link in vitro with in vivo information (employing 'cocktail' approaches if possible); reviewing co-medication sections for clinical trials; and conducting labelling-oriented interaction studies, after proof of concept. The fact that interactions can occur between various active substances should by itself be a conclusive argument against unnecessary polypharmacy. Prescribing fewer drugs on a rational basis can reduce the risk of adverse effects secondary to drug interactions and may help to improve the quality of drug treatment and to save costs.