Detection of populations at risk and problem drugs during drug development and in pharmacotherapy

Rational drug therapy requires knowledge about the ratio of risk (adverse drug reaction) to benefit (therapeutic efficacy) for all drugs to be used in humans. However, with newly marketed drugs, the risk/benefit ratio is usually not sufficiently known. Safety is often less well defined than efficacy. This is the result of the present mode of drug development. Premarketing studies are conducted in comparatively small, homogenous populations over relatively short time intervals and under standardized conditions. Only after marketing are larger, more diversified populations exposed over prolonged times, often under uncontrolled conditions. Adverse drug reactions (ADRs) are the result of either overdosage, or allergic or idiosyncratic reactions. They can be life-threatening or mild. Some of the ADRs are common (greater than 1:10); others are very rare (less than 1:1000). The overall rate of ADR occurrence in ambulatory and hospitalized patients is high enough to have significant socioeconomic consequences. Some of the risk populations can be suspected a priori: elderly, multimorbid patients and patients with compromised drug elimination who may be overdosed if the regimens are not appropriately modified. Some problem drugs may be recognized if they display one or more of the following characteristics: narrow therapeutic index, steep dose-effect relationship, nonlinear kinetics, variable bioavailability, and pharmacogenetically determined kinetics. Other individuals at risk, however, may not be readily identifiable. They develop allergic and idiosyncratic reactions after drug exposure without exhibiting easily recognizable predisposing factors. In order to determine the number of individuals so affected, and the associated drugs as quickly as possible during the developmental process, specific ADR surveillance measures are taken.(ABSTRACT TRUNCATED AT 250 WORDS)