title: Predicting the clinical relevance of drug interactions from pre-approval studies.
abstract: Drug interactions (DIs) may result in adverse drug events that could be prevented, but in many cases the available information on potential DIs is not easily transferable to clinical practice. The majority of studies date from preclinical or premarketing phases, using animals or human-derived sources that may not accurately reflect the growing clinical complexity of high-risk populations, such as the elderly, women, children, patients with chronic disease, polytherapy and impaired organ functions. Thus, at the time of approval of a new drug the information in the summary of product characteristics refers to potential DIs, but lacks specific management recommendations and is of limited clinical utility. Therefore, we set out to review in vitro and in vivo methods to predict and quantify potential DIs, to see whether these studies could help the physician tackle daily problems of the assessment and choice of combined drug therapies, and to propose, from a clinical point of view, how premarketing studies could be improved so as to help the physician at the patient's bedside. Preclinical and premarketing study design needs to be improved to make information easily accessible and clinically transferable. Studies should also take into account appropriate sample size, duration, co-morbidity, number of coadministered drugs, within- and between-subject variability, specific at-risk populations and/or drugs with a relatively narrow therapeutic window, and clinical endpoints. After premarketing development in situations where there is potential high risk of serious adverse events, specific phase IV studies (and/or active pharmacovigilance studies) should be required to monitor and quantitatively assess their clinical impact.
authors.affiliation: Laboratory of Drug Metabolism, 'Mario Negri' Institute for Pharmacological Research, Milan, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Caccia
authors.forename: Silvio
authors.initials: S
authors.lastname: Garattini
authors.forename: Luca
authors.initials: L
authors.lastname: Pasina
authors.forename: Alessandro
authors.initials: A
authors.lastname: Nobili
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D023421:Models, Animal; D008954:Models, Biological