Drug-drug interactions (DDIs) occur when the effects of one drug are altered by the presence of another drug. The effects of an interaction can be expressed in terms of how the combination of drugs affects the individual or by how the individual processes the drugs. The clinical impact of an interaction may differ according to the order in which a patient encounters the interacting drugs.
Our proposed study will focus on the use of antipsychotic drugs for the treatment of mental illness with the objective being to identify adverse DDIs when antipsychotic drugs are used in combination with other medications. The potential consequences of a DDI involving antipsychotic medication include toxic effects where the patients ability to process the antipsychotic is hindered by another drug. Other DDIs may cause the antipsychotic to be less effective in treating the patients illness. It is also important to consider how an individual patients attributes, lifestyle, and health may influence the effect of a given DDI.
The CPRD provides information on medicines prescribed and patient outcomes as they occur in routine clinical practice. This offers a valuable opportunity to evaluate and quantify the consequences of exposure to interacting drugs. We will focus on the main DDIs associated with antipsychotics - in combination with other antipsychotics and with other non-antipsychotic drug classes. We aim to quantify how frequently these interactions occur, and are captured in primary care, and to estimate the effects of key DDIs on subsequent major adverse outcomes.
The addition of another medication to an antipsychotic treatment regimen can potentially induce a pharmacokinetic and/or pharmacodynamic (PKPD) interaction. We aim to produce evidence to support or refute some of theinteractions that have been postulated via assumed bio-chemical mechanisms, but which remain unsubstantiated from an empirical perspective (Preston, 2019).
Defined DDI mechanisms are consistent: either one drug (the precipitant) causes the interaction by affecting the absorption, distribution, metabolism or excretion of another drug (the object) or there is an additive effect of the two drugs occurring via a pharmacodynamic process. A potential consequence of a PKPD antipsychotic DDI is a change in the antipsychotic (object) drugs plasma concentration, which can subsequently affect the toxicity/efficacy of the antipsychotic. It is hypothesised that many DDIs involving antipsychotic drugs are caused by additional drugs that affect the metabolism of the antipsychotic in the liver via induction or inhibition of the cytochrome P450 family of enzymes. However, an empirical evidence-base relating to the impact of these proposed interactions is lacking.
Longitudinal electronic health records provide an important resource for assessing the frequency of DDIs and for estimating the impact on risks of adverse events. We aim to utilise the CPRD and its linked datasets, to estimate the prevalence of DDIs in primary care, and to gauge the level of variation that is specific to individual general practices. We plan to use a time-dependent cohort design and self-controlled methods to identify potential risk associations between proposed DDIs and a range of adverse outcomes including major cardiovascular events.
Practice-level variation in the prevalence of proposed interactions will be quantified using mixed effects logistic regression. Risk ratios in the time-dependent cohort studies will be estimated using Cox regression models. For the self-controlled designs, the data will be analysed using matched-pair odds ratios and incidence rate ratios.
Neutropenia/agranulocytosis
Aspiration pneumonia
Major adverse cardiovascular events (MACE) incorporating specifically:
- Stroke
- Myocardial infarction
- Cardiovascular death
All-cause mortality
Darren Ashcroft - Chief Investigator - University of Manchester
Matthew Carr - Corresponding Applicant - University of Manchester
Eleni Domzaridou - Collaborator - University of Manchester
Pearl Mok - Collaborator - University of Manchester
Richard Keers - Collaborator - University of Manchester
Roger Webb - Collaborator - University of Manchester
Tjeerd van Staa - Collaborator - University of Manchester
Tony Avery - Collaborator - University of Nottingham
HES Admitted Patient Care;ONS Death Registration Data;Patient Level Index of Multiple Deprivation