the study of Drug-Drug Interactions
Drugs are a critical part of the prevention and treatment of diseases. While drug treatments are necessary for their positive impact on the quality of patients’ lives, the increasing number of drugs available on the market means a greater potential for drug-drug interactions (DDIs). Adverse drug reactions caused by individual drugs and drug combinations contribute to one of the top 10 causes of death in the United States. Several medications have been removed from the U.S. market due to severe complications from drug interactions, such as Cisapride (Propulsid®), which was removed in January 2000 due to the potential of life-threatening arrhythmias. It is not uncommon to have patients treated with multiple medications for either single or multiple conditions. Such interactions can occur with both prescribed and over-the-counter medications, as well as neutraceuticals. Clinical studies are often conducted to determine the effects of taking multiple medications, both to see the effect on systemic exposure, and investigate possible interactions.
Mechanism of Action and Metabolism
The first step is to determine how a particular drug produces its therapeutic effect and how it is metabolized. In vitro studies determine whether a drug is a substrate, inhibitor, or inducer of certain metabolizing enzymes and/or intracellular transporters, and from there it can be determined if interactions with other drugs, or even food, are likely. The next step is to conduct in vivo drug interaction studies to validate whether the nature of these interactions is clinically relevant, and will affect the patients’ health or wellbeing. Strategies to manage any interactions are also part of the clinical research conducted.
DDIs can produce life-threatening side effects, or limit efficacy, and as such are one of the most important factors to consider in drug development and clinical research. For patients taking more than one medication at a time, there is a risk that one drug may alter the effect of another, either by reducing its effectiveness or elevating systemic concentrations to potentially dangerous levels. In some cases, the outcome could be severe, such as a dangerous drop in blood pressure, irregular heartbeat, or damage to the heart or liver.
FDA Guidance on DDis
The study of drug interactions is subject to oversight by the FDA. The 2017 FDA guidance entitled Clinical Drug Interaction Studies states:
“Clinically relevant DDIs between an investigational drug and other drugs should therefore be:
- Defined during drug development as part of the sponsor’s assessment of the investigational drug’s benefits and risks
- Understood via nonclinical and clinical assessment at the time of the investigational drug’s approval
- Monitored after approval
- Communicated in the labeling
Why Conduct DDI Studies
The goals of studies that investigate metabolism- and transporter-mediated DDIs are to determine:
- Whether the investigational drug alters the pharmacokinetics of other drugs
- Whether other drugs alter the pharmacokinetics of the investigational drug
- The magnitude of changes in pharmacokinetic parameters
- The clinical significance of the observed or expected DDIs
- The appropriate management strategies for clinically significant DDIs
Sponsors should evaluate DDIs before the product is administered to patients who are likely to take concomitant medications that could interact with the investigational drug. Furthermore, sponsors should collect enough DDI information to prevent patients from being unnecessarily excluded from any clinical study because of their concomitant medication use.”
Drug interaction information is an integral part of any new drug application and needs to be summarized on the drug label. DDIs can occur between prescription medications and over-the-counter medications (antihistamines, pain relievers, and others). There are also sometimes food interactions to consider, for example grapefruit should not be eaten by people taking certain cardiovascular drugs. In order to avoid side effects and maximize the benefit of any treatment, it is recommended that when patients start a new medication, they let their physicians/pharmacists know about their use of over-the-counter drugs, and read/follow the medication label carefully.
Altasciences has helped many clients assess DDIs and food effects in the clinical setting. Our team of experts can assist in identifying what study approaches may be best suited to evaluate a new drug in development in today’s regulatory environment.
For more information or to contact our experts, please contact us today.