How Biosimulation Can Provide Insight into Herbal Supplement Safety

How Biosimulation Can Provide Insight into Herbal Supplement Safety

According to the Council for Responsible Nutrition, a trade group for the $32 billion nutritional supplement industry, 68% of adults take dietary supplements. Further analysis shows that supplement use is more prevalent among women, the children of women that take supplements, and the elderly. Like drugs, supplements do not work the same in all patients due to a range of genetic and environmental factors. And supplements are not regulated with the same rigor of as drugs. Ergo, the quality and dosage of supplements may vary widely. Moreover, herbal supplements can interact with drugs to either lessen their effectiveness or cause toxicity. Biosimulation technology, including physiologically-based pharmacokinetic (PBPK) modeling, is increasingly being leveraged to better understand drug-supplement interactions.

Weak regulatory oversight

The US FDA has little authority to review supplements prior to them appearing on the shelves of your local CVS.  What FDA can do is inspect nutraceutical production facilities for compliance with Good Manufacturing Practices, a practice that has increased since the FDA published final rules requiring compliance by 2010.  However, a look at that inspection data provides some sobering news around the issues of product quality and consistency:

  • 71% of supplement manufacturers received a Form 483 from the FDA, which is essentially a pre-warning letter citing multiple observations requiring corrective action;
  • About one third of all 626 facilities received a status of Official Action Indicated, requiring the manufacturer to address “significant conditions or practices” where regulatory action is required;
  • FDA data around adverse events point to both the increased use of supplements among adults and the negative reactions among those adults.
chart of adverse events
There has been a troubling rise in adverse events related to supplement use in the last couple of years.

Drug-supplement interactions

A recent Wall Street Journal (WSJ) article has brought attention to the issue of interactions between supplements and prescription drugs, an issue that has not been well studied. The article points out that recent studies found that more supplements than previously thought can impact the way certain enzymes metabolize drugs. For example, they may inhibit the enzyme’s ability to break down a drug and impact clearance, causing the prescription medicine to build up to the point of potentially causing an overdose. Couple these findings with data from the Council for Responsible Nutrition that as many as 70% of patients don’t tell their physician about their use of supplements and doctors don’t usually ask when taking a medical history.

An area of specific concern raised in the WSJ article is among cancer and surgery patients and those on heart and blood thinner medications, where there are small differences between beneficial and toxic doses. While we know about the impact of St. John’s Wort and its side effects when taken with certain anti-depressants or interference with contraceptives and HIV medications, the article cites a warning from the director of the UCLA Center for East-West Medicine on popular supplements like ginger, garlic, ginseng, and gingko as interacting with blood thinners. Another example is the popular sleep supplement, Kava, which can potentially reduce the efficacy of breast cancer drugs.

Role of modeling and simulation

While the study of drug-supplement interactions is relatively new, there is ample opportunity for biosimulation to answer key safety questions. A recent article published by a team of scientists from Washington State University and the University of North Carolina used modeling and simulation to evaluate silibinin, a semi-purified milk thistle seed extract taken with raloxifene, a selective estrogen receptor modulator. Milk thistle is a popular supplement that is reputed to detoxify and protect vital liver function. Raloxifene was selected as a clinically relevant exemplar of an intestinal UDP-glucuronosyl transferases (UGT) substrate.

To test a proof-of-concept clinical study, a Simcyp PBPK model was built based on a virtual cohort of 16 healthy patients, aged 18 to 65 years, with raloxifene (60 mg) and silibinin (480 mg three times daily) administered in the fasted state. Pharmacokinetic outcomes were recovered by non-compartmental analysis using Phoenix WinNonlin. The Simcyp model leveraged the ADAM model, which uses a mechanistic framework to describe the passage of drug molecules along and through the gastrointestinal tract. The ADAM module divides the intestine into multiple transit compartments, distributing any drug-supplement interactions of the silibinin perpetrator and the drug victim, raloxifene along the entire gastrointestinal tract.

The Simcyp model predicted negligible changes in raloxifene pharmacokinetic outcomes and rapid silibinin elimination. However, there were some subjects that demonstrated an almost two-fold increase in raloxifene exposure, suggesting further investigation is warranted. PBPK modeling should further be iterated with clinical data when possible to understand the full impact of drug-supplement interactions.

Next steps

With recognition of possible negative health impacts of mixing supplements and pharmaceuticals against a rising tide of supplement usage, the need for further study is clear. The University of Illinois is working in this area and has recently obtained funding from the NIH to study the impact of certain supplements and common prescriptions used in women’s health. Specifically, clinical studies are planned to evaluate supplements such as licorice, hops and red clover, used to relieve menopause symptoms and potential interactions with high blood pressure and cholesterol medicines. That same Illinois team is evaluating biosimulation options to study drug-supplement interactions.

When you couple the issues of product quality stemming from limited regulatory oversight with our lack of knowledge around drug-supplement interactions, we should expect increased scientific rigor placed on this field. Interestingly, recent television advertisements for certain new drugs remind patients to tell their physicians about not only the drugs they take, but the supplements they use in the disclaimer statement at the end of each commercial.


References

[1] The Wall Street Journal, February 29, 2016. “How your supplements interact with prescription drugs.” By Laura Landro

[2] Contract Pharma, March, 2016, page 22. “Are your nutritional supplements safe?” By Ben Locwin

[3] CPT Pharmacometrics Systems Pharmacology (2015) 4, 701-710. “Quantitative prediction and clinical evaluation of an unexplored herb-drug interaction mechanism in healthy volunteers.” By BT Gufford et al

[4] AAPS Journal, 11, 225-237 (2009). “Population-based mechanistic prediction of oral absorption.” By M Jamei, et al


All information presented derive from public source materials.

Learn more about how PBPK can help determine the mechanisms of drug-drug interactions

PBPK modeling supports investigating the mechanisms of DDIs. Read this case study to learn how Certara scientists applied PBPK modeling to understand complex DDIs, both for drugs in development and following marketing approval.

Ellen Leinfuss

About the Author

Ellen Leinfuss

Senior Vice President & Chief Commercial Officer, Certara

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Ms Leinfuss brings more than 25 years of experience leading marketing, business development and sales management groups for technical and scientific-based organizations. She spent the last nine years at UL EduNeering, a global provider of regulatory compliance educational solutions, delivered via cloud-based technology. At UL, Ms. Leinfuss directed the strategic development of the company’s solutions to the life science market, including pharmaceutical, medical device, biologics, clinical, and managed care health plans. In addition, she managed the Company’s strategic alliances, including the Company’s 15 year Cooperative Research and Development Agreement (CRADA) with the US FDA and its exclusive partnerships with AdvaMed and the Personal Care Products Council, among others. Ms Leinfuss possesses a Master's in Business Administration in marketing from the City University of New York and Bachelor's in Chemistry from the State University of New York.