Food–drug interactions risk management: An emergent piece of pharmacovigilance systems

The healthcare model has evolved over the years to embrace patient‐centered care, aiming to encompass all dimensions of patients when tailoring therapeutic plans. This approach should incorporate a comprehensive review of the patient's medications, among other considerations, to assess the potential for drug interactions that might increase adverse effects or result in therapeutic failure. Nevertheless, drug interactions include not only interactions between different drugs but also interactions between drugs and food, its components, dietary supplements, and herbal products.

The most described food–drug interactions are linked to pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics. Examples of these responses are the absorption and bioavailability changes throughout the gastrointestinal tract; the enzymatic induction/inhibition in drug metabolization, namely, cytochrome P450; or transporters modulation, like P‐glycoprotein; among others. These modifications in pharmacological activity can represent changes in concentration at the receptor level and modified drug responses at the pharmacological target. However, drug–herb interactions are increasing the knowledge about these issues, with many healthcare providers having no perception of this potential problem, a fact that reflects the lack of training on this topic and the paucity of real‐world evidence. ¹

Some authors emphasized the importance of increasing the stakeholder's awareness about this health issue, food–drug interaction as a serious adverse reaction risk. The food–drug interactions, drug–nutrient interactions, and drug–herb interactions here generically referred to as food–drug interactions have been identified and described as fundamental risk management contents. These interactions assume new dimensions and complexity since patients, many times with comorbidities, take several dietary supplements and medication simultaneously. ¹ , ²

Another factor that contributes to this problem is related to the general idea that food and dietary supplements are safe if they are natural, and based on this opinion and false perception of safety, it is estimated that about 70% of patients do not report the consumption of this supplements to their healthcare providers, namely, due to not recognizing the importance of this information. Additionally, the increased risk of interactions is promoted by the increased popularity of dietary supplements, natural products, functional foods, and health foods among consumers. Identifying and avoiding potential food–drug interactions will help the treatment optimization and counseling improvement. ³ , ⁴ , ⁵ These interactions are not unilateral, it is not only the potential of food products to interact with drug effects but also drugs can interfere with alimentary physiology, namely, with the absorption of essential nutrients. ²

However, despite increasing knowledge on this topic, many healthcare professionals do not perceive food–drug interactions as a potential problem and food–drug interactions still represent an under‐recognized source of medication errors and adverse reactions due to changes in the pharmacokinetics and pharmacodynamics of drugs. This fact reflects the lack of training on this topic and the paucity of real‐world evidence. ¹ According to the European Medicines Agency (EMA), a medication error is an unintended failure in the drug treatment process that leads to or has the potential to lead to, harm to the patient.

These errors imply pharmacological failures, with several constraints to safe and effective pharmacotherapy and eventually malabsorption problems, and consequent nutritional deficits. ⁶ , ⁷

Obtaining information related to food–drug interactions is demanding and complex. The underreporting, namely, linked to the challenges in identifying food–drug interactions and the lack of awareness regarding the reportability of such interactions, represents an identified phenomenon, which should be attended to by the risk management systems, especially focused on proactive and spontaneous pharmacovigilance. ² , ⁷

From this point of view, it is emergent to consider a clear plan to integrate this information and this vigilance into the national and international pharmacovigilance systems, assuming an active role of data and evidence generators, like as already largely assumed to the general concept of adverse drug reactions (Figure 1).

FIGURE 1.

Global overview of the future of pharmacovigilance (Adapted from the author Advinha et al. ⁸ ).

Regarding the model proposed in Figure 1, integrating the food–drug interactions and their outcomes in pharmacovigilance should be intuitive, although the complexity represents a barrier on this matter, namely, due to the several compounds involved. It is important to recall that pharmacovigilance represents the science and activities related to the detection, assessment, comprehension, prevention, and communication of drug risk management, namely, adverse drug reactions including food–drug interactions. This fact implies the monitorization and evaluation of the medicines and patient safety concerns, predominantly during post‐marketing surveillance. ⁵ , ⁹ It is also important to bear in mind that the information from pre‐marketing randomized clinical trials is limited in all aspects, with a special focus on sample representativeness. This is also true for food–drug interactions and significantly more complex due to different alimentary patterns and profiles. Moreover, ignoring the intake of potential foods/supplements that produce drug interactions among participants in clinical trials can result in considerable variability in the outcomes. ³

Translating the reflections to practical examples and problems, it is important to refer to the major medication‐related issues that contribute to intensifying the challenges posed by food–drug interactions. Some adverse events resulting from these interactions are based on single reports, with several biases and confounding factors. If you imagine the number of food–drug adverse events that remain unreported and multiply by the number of drugs and food compounds consumed by each patient, an enormous number of potentials is anticipated. To illustrate this consideration, take as an example Péter et al. ¹⁰ publication and the attention provided to food–drug interactions as a public health problem. Degefu et al. also discussed the overall unfavorable outcomes of these interactions during patient treatment. ⁶ Typical scenarios of elevated risk encountered in routine practice, include aging, polypharmacy, comorbidities, specific conditions like transplant recipients or cancer patients, malnutrition, infections, and patients receiving enteral or parenteral nutrition, among many others.

The absence of a clear definition of risk prevention and the lack of evidence‐based information available to healthcare providers and patients/consumers represents a low action about the safety of taking drugs concomitantly to certain foods and/or supplements. An integrated and robust framework for assessing food–drug interactions and translating the data into changes (e.g., formulation, dose, labelling, and/or post‐marketing surveillance strategies) is needed. ⁵ , ¹¹

Three start points can be (i) understanding the molecular basis of food ingredients, and the composition of herbal products and dietary supplements; (ii) determining the interaction between bioactive drugs and food compounds with genes; and (iii) training the human and artificial intelligence to support the clinical interventions, namely, to prevent the interactions with personalized approaches. Clear communication and dissemination of knowledge can constitute measures not only to promote patient engagement but also to involve healthcare providers and researchers in a common aim, contributing to evidence generation and translation to daily practice. In all cases, tools like machine and deep learning associated with big data and bioinformatics could be determinant. ⁷

However, there are tools to assess drug–drug and food–drug interactions. Some reliable websites offer interaction checker applications accessible to both professionals and the public, enabling them to examine specific interactions. Nevertheless, it is crucial to note that the information provided by such resources lacks clinical context. A detailed clinical evaluation is always needed to accurately gauge the potential for interaction. Interactions may vary among patients, and it is the healthcare provider's responsibility to distinguish between the risk of an interaction and the real danger to the patient's health if such an interaction occurs. It is imperative to differentiate between possible or theoretical potential interactions, determine the minor or major extension, and assess the potential outcomes of the event. Based on this assessment, appropriate monitoring methods may be developed for risk minimization, for example, discontinuation of one or more of the implicated products. ¹ , ³

Healthcare teams play a key role in preventing food–drug interactions; therefore, the expansion of their knowledge regarding the prevention of potential adverse events is essential. However, the information available about how well healthcare providers know about food–drug interactions is still poor. Some studies identified inadequate knowledge but have not identified real measures to improve performance. ⁶ So, educational measures, like specialized courses and clinical training, should be promoted to improve knowledge and its implementation.

The ability to identify and prevent food–drug interactions could be an important contribution to medication effectiveness and safety, with the aim of successful health and well‐being outcomes, according to the patient individual care plan. The inclusion of this topic into research and clinical agenda could represent an improvement to the practical implementation by healthcare providers and patients. In this perspective, pharmacists have an essential role in identifying and monitoring potential safety and effectiveness issues. Although food–drug interactions appear as a relevant public health topic, they still underestimate, where it is emergent to keep an eye on, generating real‐world evidence.

Hence, conducting new studies is urgent to enhance healthcare providers' comprehension of the implications of food–drug potential interactions. Research including the safety and efficacy of food/dietary supplements and medications coexisting should encompass a comprehensive analysis of the metabolism of major active compounds. Additionally, exploring the potential interactions in clinical routine is essential for assessing safety and effectiveness. This evaluation should be developed under conditions reflecting recommended daily doses and frequency consistent with typical usage, of both drugs and food.

Until more reliable studies become accessible, healthcare providers and patients should know and assess the existing information to determine the most effective approach, with a focus on the pharmacovigilance principles of a patient‐centered approach.

AUTHOR CONTRIBUTIONS

In this collaborative effort, AMA, JPF, and MP equally contributed to the collective reflection, literature review, writing, and revision of this document.

CONFLICT OF INTEREST STATEMENT

None.

ETHICS STATEMENT

Not applicable.

Advinha AM, Fernandes JP, Perdigão M. Food–drug interactions risk management: An emergent piece of pharmacovigilance systems. Pharmacol Res Perspect. 2024;12:e1245. doi: 10.1002/prp2.1245

DATA AVAILABILITY STATEMENT

None.