In vitro testing for diagnosis of idiosyncratic adverse drug reactions: Implications for pathophysiology

Abstract

Idiosyncratic drug reactions (IDRs) represent a major health problem, as they are unpredictable, often severe and can be life threatening. The low incidence of IDRs makes their detection during drug development stages very difficult causing many post-marketing drug withdrawals and black box warnings. The fact that IDRs are always not predictable based on the drug's known pharmacology and have no clear dose-effect relationship with the culprit drug renders diagnosis of IDRs very challenging, if not impossible, without the aid of a reliable diagnostic test. The drug provocation test (DPT) is considered the gold standard for diagnosis of IDRs but it is not always safe to perform on patients. In vitro tests have the advantage of bearing no potential harm to patients. However, available in vitro tests are not commonly used clinically because of lack of validation and their complex and expensive procedures. This review discusses the current role of in vitro diagnostic testing for diagnosis of IDRs and gives a brief account of their technical and mechanistic aspects. Advantages, disadvantages and major challenges that prevent these tests from becoming mainstream diagnostic tools are also discussed here.

Keywords: adverse drug events; adverse drug reactions; drug allergy; idiosyncratic drug reactions; in vitro diagnosis.

Figure 1

Classification of adverse drug reactions (see text for details)

Figure 2

Molecular mechanisms of immune mediated idiosyncratic drug reactions demonstrating the principle of the lymphocyte toxicity assay (LTA), the in vitro platelet toxicity assay (iPTA), the basophil activation test (BAT) and the lymphocyte transformation test (LTT). (A = Activation); (D = detoxication); non-reactive parent drug (); reactive parent drug (); reactive metabolite ()