Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

BACKGROUND: Adverse drug reactions are sometimes described as being 'non-dose-related' because no relationship has been found between increasing doses and either the intensity of the response or the proportion of individuals in whom the response occurs; furthermore, hypersensitivity reactions are often regarded as being non-dose-related, even if different doses have not been studied. However, the law of mass action implies that all pharmacological effects are concentration related and should increase in intensity with increasing dose. We set out to explain this paradox. METHODS: We searched for published adverse drug reactions that have been described as non-dose-related and analysed them. RESULTS: We identified four categories of explanations that resolve the paradox: (i) the reaction is not real; it may have occurred by chance or there may be methodological problems, such as bias or confounding factors; (ii) the dose-response curve for the adverse effect reaches a maximum at doses lower than were studied (i.e. a hypersusceptibility reaction); this underpins the use of test doses to predict the possibility of an adverse reaction at therapeutic doses; (iii) susceptibility to the adverse reaction differs widely among individuals; and (iv) imprecision or inaccuracy in the measurement of either dose or effect obscures dose responsiveness. This last explanation encompasses: (a) reactions related to cumulative dose; (b) dissociation between dose and concentration through saturable pharmacokinetics; and (c) variability in the measurement of the effect. CONCLUSIONS AND IMPLICATIONS: If an adverse drug reaction appears to be non-dose-related, the reasons should be sought, having these mechanisms in mind.

Original publication

DOI

10.1111/bcp.12706

Type

Journal article

Journal

Br J Clin Pharmacol

Publication Date

01/2016

Volume

81

Pages

56 - 61

Keywords

dose-response relationship, drug-related adverse effects, drug-related adverse reactions, law of mass action, Animals, Dose-Response Relationship, Drug, Drug-Related Side Effects and Adverse Reactions, Humans