Can the rise in drug-drug interactions be halted, or is it an inevitable side effect?

The trend towards patients taking several medications at the same time is increasing, especially with the ageing population, giving rise to a corresponding rise in the possibility of adverse reactions. What can be done to minimise the risks to patients and companies?

Unanticipated adverse drug-drug interactions (DDIs) have led to the withdrawal of several high-profile drugs that had been available for a number of years. All were linked to potentially fatal arrhythmias among other effects, when co-administered with certain other medications. The most recent data available from the US National Center for Health Statistics (NCHS) shows rising prescription drug use in the US. DDIs are likely to increase as more drugs and drug combinations are used to treat patients.

"By 2008, 40 per cent of adults aged 60 and over used five or more prescription drugs in a one-month period"

The rate of adverse drug events due to DDIs increases exponentially once a patient is on four or more medications. Figures from 2010 revealed that over three-quarters of doctor visits involved drug therapy (at least one medication provided, prescribed or continued) and over the past decade the use of multiple prescription drugs increased by 20 per cent overall. By 2008, 40 per cent of adults aged 60 and over used five or more prescription drugs in a one-month period. The challenge of a global ageing population can only make the problem of DDIs worse.

The industry is trying to address this issue during preclinical and clinical testing. The US Food and Drug Administration (FDA) has published draft guidance on drug interaction studies and their implications for study design, data analysis, dosing and labelling recommendations. Technology also has a significant part to play in supporting preclinical compound prioritisation and providing better insights before the launch of clinical trials.

Decision support tools can help uncover the information required to establish inclusion and exclusion criteria for patients who wish to participate in trials. Analyses may lead to the exclusion of patients taking a particular drug likely to interact with the investigational compound; or the identification of a drug similar to one that patients are already taking, but which is unlikely to trigger a DDI with the new entity. The latter scenario would enable patients who might not otherwise be eligible for a study to participate safely.

Although such efforts can be effective, they can fall short if any critical data is missing. Most risk-mitigation analyses are run on comparative databases made up largely of information from the literature and labelling. Adding regulatory data from the medical, chemistry, statistical and clinical pharmacology/biopharmaceutics reviews sections of the FDA's new drug approval packages, and similar input from the European Medicines Agency (EMA) to the data for analysis can help ensure that important human information is not missed. The studies referenced in these FDA and EMA documents are not published, but if they are not reviewed during preclinical and clinical testing it could potentially result in a drug being withdrawn from the market because of unanticipated DDIs.

"Delving deeper than the approval letter and labelling is vital for designing DDI and clinical studies to prevent unexpected adverse events sooner"

The approval package for the non-nucleoside reverse transcriptase inhibitor nevirapine provides relevant examples. Delving deeper than the approval letter and labelling, into the 'clinical comment' section, yielded significant information: 1) co-administration with fluconazole can lead to an increased risk of a life-threatening adverse event due to overexposure to nevirapine; 2) not recommended to be administered together with ketoconazole due to decreased efficacy of same; and 3) need for caution when co-administering with rifabutin because some subjects will experience adverse events. This kind of information is vital for designing DDI and clinical studies to prevent unexpected adverse events sooner and for recommending optimal dosage and timing of that dosage for patients that use more than one prescription drug.

"Cutting a dose in half or putting a warning on a label might mitigate risk from a scientific perspective, but the risk to the business might remain unacceptable"

From a business perspective, this comparative analysis must be done before any new entity is prescribed, so companies are prepared for any potential consequences that can affect a new drug's competitive position. Cutting a dose in half or putting a warning on a label might mitigate risk from a scientific perspective, but the risk to the business might remain unacceptable. For example, does it make sense to produce a new cancer drug that is as effective as, or slightly more effective than, current treatments, but can't be used with a doctor- or patient-preferred antiemetic?

A recent study showed the level of evidence used to support drug withdrawal decisions in Europe has improved over the past 10 years, with an increased use of case-control studies, cohort studies, randomised controlled trials and meta-analyses. Similarly, the level of evidence used to assess the scientific and business risks of DDIs before new drugs reach the market needs to be as deep and comprehensive as possible; drug developers need to be able to drill down into all relevant studies, published or not, to extract every bit of actionable data.

About the author:

Philip MacLaughlin, is director - product development at Elsevier R&D Solutions for Pharma and Life Sciences. He has been a product manager focused on commercial pharmaceutical research and development for 16 years, both at Elsevier and previously at MDL. He has developed and managed content products pertaining to drug safety, pharmacokinetics and metabolism, and analytical products such as a QSAR suite and various standalone commercial predictive modelling algorithms. He was a principal investigator in a cooperative research and development project with the US FDA from 2000 – 2003.

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