Health professionals and others have expressed varying degrees of interest and concern regarding the potential for clinically relevant interactions between conventional pharmaceutical medications and dietary supplements, including herbal products.1,2 Considerations such as history of safe use (within the context of traditional versus modern usage), literature data from pharmacology and toxicity studies, and constituent quantities in supplements provide some guidance on whether to assess herb-drug interactions (HDIs) experimentally. The scientific literature is replete with pre-clinical reports of various herbal extracts and constituents as potent inhibitors of drug-metabolizing enzymes (Table 1).3-6 However, without the use of appropriate analytical methods for herbal product characterization and quantitation of constituents, dose performance analysis, or in vitro testing in physiologically relevant models to allow some prediction of bioavailability of key constituents, extrapolating these reports to determine whether human testing is necessary to identify clinically relevant HDIs is difficult. This lack of a clear determination of risk hinders clinicians and consumers from making informed decisions about the safety of taking herbal products with conventional medications. A suitable framework is needed that describes a flexible approach for assessing when human HDI studies are warranted, as well as an outline of standard methods when HDI testing is conducted.
Herbal product usage in Western countries continues to increase across all age groups.7,8 Individuals in these countries also have ready access to conventional medications, and significant polypharmacy is often observed, particularly in women and older adults.8,9 Many patients are reticent to disclose herbal product usage to their healthcare providers, and many providers still do not inquire about such usage. In addition, many healthcare professionals are now recommending herbal products to counteract side effects of some conventional drugs.10 Thus, the potential for both HDIs and drug-drug interactions is frequently ignored in clinical practice because of the complexity of the problem. The net result is that the opportunity for clinically significant HDIs exists and should be evaluated in a systematic manner.
Although dietary supplements and herbal products in most countries are not subject to the same regulatory guidelines for pre-market testing as conventional drugs, there is an increasing focus by many regulatory agencies on the potential for HDIs. Likewise, consumers have an increased awareness of HDIs as a result of numerous media reports. Providing accurate information on potential HDIs facilitates informed decision-making by consumers and healthcare providers alike.
There are an increasing number of scientific papers related to the field of HDIs. However, most studies utilize simple in vitro metabolic systems (e.g., liver microsomes), and the results often are too unreliable to provide meaningful assessment of clinically relevant HDI potential. The in vitro exposure to the complete phytochemical complexity of an herb or herbal extract does not represent the systemic exposure to the ingested and altered phytochemical matrix or its limited absorption and variable distribution. Thus, most of these reports are preliminary and often do not attempt to define the clinical relevance of such findings. There is little follow-up work conducted in more complex in vitro systems such as whole-cell hepatocytes with fully functional transporter and metabolizing enzymes, or the use of physiologic-based pharmacokinetic (PBPK) models to extrapolate to in vivo relevance. Won et al. recently reviewed a number of dietary substance-drug interactions in which both in vitro and clinical data exist, and in many cases there was no correlation of findings.11 In addition, there is sometimes poor analytical characterization of the botanical materials used, contributing in large part to inconsistent findings across studies.
In the prescription medicine world, there is clear guidance on how to assess potential drug-drug interactions.12,13 Because there is no standard/systematic regulatory guidance on testing for HDI potential, there is an opportunity in the scientific community to lead the way in establishing such a framework.
From a dietary supplement industry perspective, an ideal framework approach for assessing HDI potential would include the following criteria (summarized in Figure 1):
A screening approach that can encompass a pipeline (i.e., “higher throughput”);
Cost and resource efficiency;
Readily transferable to external partners (e.g., contract research organizations) since many companies do not have the internal expertise and/or testing facilities;
Consistent application across the industry;
Inclusion of a decision tree to determine when more in-depth studies may be warranted (e.g., a tiered approach);
Guidance on how to design and interpret studies; and
Guidance on how to apply HDI information to dose adjustment, labeling, and/or post-marketing surveillance strategy.
Furthermore, there are a number of important considerations that should be included within each component (Table 2). Follow-up studies may be warranted in situations where there is an inconsistent history of safe use or insufficient literature data on HDI potential, e.g., if there is no data available on cytochrome P450 (CYP450)/transporter inhibition/induction potential, or literature data reporting potent in vitro inhibition of CYP450/transporters. When testing is necessary, one can refer to the drug-drug interaction guidances of the US Food and Drug Administration and European Medicines Agency.12,13
In summary, there is a need to form an academia/industry/regulatory-wide expert working group to develop a framework for assessing HDI potential. Expertise is needed in diverse areas including in vitro metabolism/transporter studies, PBPK modeling, clinical pharmacokinetics, analytical chemistry, biopharmaceutics, and risk assessment. The goal would be to develop a comprehensive strategy that incorporates these key components into an overall HDI risk assessment that facilitates informed decision-making by consumers and healthcare providers.
The topic of assessing HDI potential was highlighted at the 41st Annual Summer Meeting of the Toxicology Forum in July 2015. A plenary presentation, titled “Assessing Potential Natural Product-Drug Interactions: Need for a Common Framework Approach,” was given by a number of experts in this field that further described the concepts captured herein. Details related to this meeting can be found at: http://toxforum.org/next_meeting.
Amy L. Roe, PhD, is a senior toxicologist in the personal healthcare division at The Procter & Gamble Company in Cincinnati, Ohio. She received her PhD in toxicology from the University of Kentucky in 1997 and conducted post-doctoral work at the University of Cincinnati. Her expertise includes general and regulatory toxicology, drug/xenobiotic metabolism, and pharmacokinetics. She is a diplomate and current board member of the American Board of Toxicology, and serves as councilor on the Regulatory and Safety Evaluation Specialty Section of the Society of Toxicology. She can be contacted at roe.al@pg.com.
Disclosure
The Procter & Gamble Company is a distributor of dietary supplement products.
Acknowledgements
The author would like to acknowledge discussions and input to this framework approach from Mary Paine, PhD (Washington State University), Bill Gurley, PhD (University of Arkansas for Medical Sciences), Rick Kingston, PharmD (SafetyCall International), Hellen Oketch, PhD (United States Pharmacopeia), and James Griffiths, PhD (Council for Responsible Nutrition).
References
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