Mechanism-based drug exposure classification in pharmacoepidemiological studies

Abstract

Mechanism-based classification of drug exposure in pharmacoepidemiological studies In pharmacoepidemiology and pharmacovigilance, the relation between drug exposure and clinical outcomes is crucial. Exposure classification in pharmacoepidemiological studies is traditionally based on pharmacotherapeutical reasoning, but other classification schemes on the basis of molecular characteristics, pharmaceutical formulation or pharmacological mechanisms are also possible. The objective of this thesis was to evaluate the role of structure-activity relationships in the understanding and prediction of drug-related safety problems. In post marketing surveillance and drug safety studies, the focus lies on the detection of a disproportional reporting of a combination of a drug and an adverse drug reaction (ADR). Whether a combination of a molecular characteristic and an ADR will be observed, remains the question. Therefore, we assessed the association between molecular and pharmacological drug properties in relation with the occurrence of ADRs to expand existing knowledge about the underlying mechanisms. In seven pharmacoepidemiological studies, using data from a number of data sources, containing different kind of information, namely the General Practice Research Database, PHARMO RLS, the Utrecht Patient Oriented Database, the database of the Netherlands Pharmacovigilance Centre Lareb and the database from the International Drug Monitoring Program of the World Health Organization. In three studies, we focused on molecular drug characteristics. Substituents of the ‘sulfa’ group in sulfonamide antibiotics and sulfonamide non-antibiotics, spectroscopic parameters of drug molecules and the presence of fluorine atoms were regarded as exposure variables. We evaluated whether these variables were associated, respectively, with an increased risk of allergic reactions, photosensitivity reactions and ADRs in general. In addition, target-orientated drug exposure classification was used to assess the association with affects on kidney and ear tissues, the risk of osteoporotic and non-osteoporotic fractures, and the risk of female genital tract, gastrointestinal and intracranial bleeding. Drugs were classified according to their affinity for ion transport systems in kidney and ear tissues or their degree of inhibition of the serotonin (5-HT) reuptake inhibitor or 5-HT2A receptor. We also assessed whether there was a difference between cytostatic drug regimens formulated with or without lipophilic solvents and their influence on circulating red blood cells. In these studies, we demonstrated that is was feasible to use a mechanism-based drug exposure classification to support or confirm previous findings in drug safety studies. Furthermore, it is a useful concept to enhance knowledge about underlying mechanisms and to generate new hypotheses about underlying mechanisms in the association between a drug and an ADR. Health care professionals should be aware of these underlying biological mechanisms and the importance of molecular characteristics because this information may contribute information in the analysis of adverse drug effects and the reporting of suspected ADRs to pharmacovigilance centres.