National Center for Complementary and Alternative Medicine (NCCAM)

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Systematic Evaluation of Dietary Supplement/Drug Interactions

Project Concept Review

Council Date: June 1, 2012

Program Officer: D. Craig Hopp, Ph.D.

Background

The National Health Interview Survey (NHIS) continue to show that dietary supplements (DS) are consumed by millions of people for a variety of reasons. Furthermore, about 20-30% of patients on prescription medication indicate they are also taking DS concomitantly. In the late 90s reports emerged regarding severe and life threatening interactions between St. John’s Wort and grapefruit juice and a variety of pharmaceuticals (Rx). This led to widespread concerns about potential interactions with other DS. Subsequently, numerous reports emerged describing possible interactions between large numbers of DS/Rx pairs. However, the evidence for many of these purported interactions was in preclinical models, case studies, or based on purely hypothetical arguments, leading to questions about their clinical relevance. Nevertheless, multiple public resources continue to warn against the use of DS in combination with various Rx as a precautionary measure. Additionally, some research studies suggest that combining DS with Rx can be beneficial in certain contexts. This has resulted in much confusion on the part of consumers and health care providers.

NCCAM organized a workshop entitled “Dietary Supplement Drug Interactions” on March 27, 2012. The panel findings can be summarized into five broad conclusions. First, the field of pharmacology is sufficiently advanced such that the necessary tools are available to sensitively and accurately quantify the interactions between any DS/Rx pair. Second, in vitro research is a reasonable approach to screen for possible interactions and prioritize for future clinical investigation. Third, animal models offer little insight into the clinical significance of potential interactions and should be avoided. Fourth, human subject studies are necessary as the only way to assess the clinical significance of an interaction. Finally, the field would benefit from a clear focus and direction to allow for a more systematic evaluation of potential interactions.

Purpose Of Proposed Initiative

The evidence for interactions between specific dietary supplements and pharmaceuticals is extremely variable. High quality data from controlled human subjects studies is rare, and even then questions remain about the clinical relevance of the findings. Based on current information, fears that concomitant use of DS and Rx would produce widespread severe risks to patients appear to be unfounded. While it is entirely possible that a new supplement could emerge on the market with the potential for severe drug interactions, of greater concern currently is the characterization of non-life-threatening interactions which are poorly understood. The clinical consequences of such interactions are unknown in many instances and may have an impact on the course of treatment, outcomes, and quality of life. NCCAM is considering a phased initiative which would allow for the systematic in vitro and in vivo characterization of potential interactions between DS and Rx. Ultimately, this initiative will result in a repository of carefully controlled experiments and their results allowing for subsequent rational assessment of the relative risks and/or benefits of selected DS/Rx combinations. It should also provide a more in depth understanding of the pharmacokinetic and metabolic pathways for a large number of DS.

Objectives

The objectives of this initiative are three-fold. The first phase will establish the framework for carrying out the necessary research. This will include a comprehensive search and critical evaluation of existing literature to identify criteria for prioritization. Application of those criteria will identify high impact supplements, pharmaceuticals, DS/Rx/disease groupings, and assays which will be used to create a testing matrix for evaluation using moderate to high throughput screening. This process may also identify certain combinations for which advancing directly to human subjects research is appropriate based on the existing literature.

The second phase of this initiative involves the implementation of the in vitro and in vivo research prioritized through Phase I. If specific methodological gaps are identified these will also be addressed in Phase II. This may include development or optimization of certain assays for high throughput screening efforts or validated methods for the analysis of metabolites in various biospecimens. It is envisioned that the in vitro portion of Phase II will accommodate a large number of screens. These may include the ability of DS to inhibit or induce various metabolizing enzymes and transporters. Other screens will test combinations of DS and Rx in a battery of assays including phase I and phase II metabolizing enzymes, transporters, etc. The objective of this phase of the initiative is to identify potential high impact interactions which will then be prioritized for clinical evaluation. Furthermore, it may generate numerous other hypotheses regarding ways in which DS may be rationally combined with Rx to improve patient therapy.

Phase III will involve dissemination of the information. This will be implemented in parallel with Phase II to first capture the data generated. Details about the products tested and the degree of interaction will be tabulated and made available to the public. Through consultation and collaboration with the FDA we expect to have guidance regarding interpretation of the data and its impact on FDA guidelines for drug labeling. Furthermore, NCCAM will employ this information to educate the health care community so that more informed decisions can be made regarding patient care.