Modeling Pharmacokinetic Natural Product–Drug Interactions for Decision-Making: A NaPDI Center Recommended Approach

Cox, Emily J.; Tian, Dandan; Clarke, John; Rettie, Allan E.; Unadkat, Jashvant D.; Thummel, Kenneth E.; Paine, Mary F.

doi:10.1124/pharmrev.120.000106

Cited by 8 publications

(13 citation statements)

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“…Consumers tend to falsely equate natural with safe, and, in the US, may also incorrectly assume that the federal government requires commercial botanical products to be vetted for efficacy and safety ( 116 , 117 ). Examination of possible pharmacogenetic risk factors related to botanical metabolism and/or adverse drug-botanical interactions can therefore be important elements of botanical clinical trial design, particularly for government funded studies ( 118 , 119 ). This is particularly true when studying populations at higher risk of adverse effects due to underlying chronic disease and/or concurrent use of pharmaceuticals, as, for example, has been reported for concurrent use of certain dietary supplements with breast cancer chemotherapy ( 11 , 120 , 121 ).…”

Section: Prioritizing Public Health and Safetymentioning

confidence: 99%

Perspective on Improving the Relevance, Rigor, and Reproducibility of Botanical Clinical Trials: Lessons Learned From Turmeric Trials

Funk

Schneider

2021

Front. Nutr.

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Plant-derived compounds, without doubt, can have significant medicinal effects since many notable drugs in use today, such as morphine or taxol, were first isolated from botanical sources. When an isolated and purified phytochemical is developed as a pharmaceutical, the uniformity and appropriate use of the product are well defined. Less clear are the benefits and best use of plant-based dietary supplements or other formulations since these products, unlike traditional drugs, are chemically complex and variable in composition, even if derived from a single plant source. This perspective will summarize key points–including the premise of ethnobotanical and preclinical evidence, pharmacokinetics, metabolism, and safety–inherent and unique to the study of botanical dietary supplements to be considered when planning or evaluating botanical clinical trials. Market forces and regulatory frameworks also affect clinical trial design since in the United States, for example, botanical dietary supplements cannot be marketed for disease treatment and submission of information on safety or efficacy is not required. Specific challenges are thus readily apparent both for consumers comparing available products for purchase, as well as for commercially sponsored vs. independent researchers planning clinical trials to evaluate medicinal effects of botanicals. Turmeric dietary supplements, a top selling botanical in the United States and focus of over 400 clinical trials to date, will be used throughout to illustrate both the promise and pitfalls associated with the clinical evaluation of botanicals.

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Section: Prioritizing Public Health and Safetymentioning

confidence: 99%

Perspective on Improving the Relevance, Rigor, and Reproducibility of Botanical Clinical Trials: Lessons Learned From Turmeric Trials

Funk

Schneider

2021

Front. Nutr.

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“…Consequently, the NaPDI Center developed decision trees to guide the determination of whether clinical pharmacokinetic studies are warranted. 12 Briefly, if there are no in vitro data available but an NPDI is suspected, mechanistic in vitro studies involving established probe drugs and model systems should be conducted as described 13 , 15 (Figure 2 ). The advantage of these studies is that results can be extrapolated to other drugs metabolized or transported by the probed enzymes and transporters.…”

Section: When Are Clinical Natural Product‐drug Interaction Studies W...mentioning

confidence: 99%

“…The time of day the NP is administered should be defined based on common usage. The pharmacokinetics of an NP selected for a phase 0 study often are completely uncharacterized, but some pharmacokinetic end points and even concentration‐time profiles may be predicted from biophysical data using contemporary software, 15 , 22 allowing researchers to align sampling windows with the predicted maximum concentration of an uncharacterized phytoconstituent. This technique also can be used to derive estimates of the clearance of a given phytoconstituent to guide the duration of sample collection during the terminal elimination phase.…”

Section: Phase 0 Clinical Study Designmentioning

confidence: 99%

“…The crux of the decision to conduct a clinical pharmacokinetic NPDI study is rooted in the results obtained from predictive static and/or PBPK models. 15 This decision point is considered crucial due to the substantive resources required to conduct clinical studies. Additional factors contribute to the uncertainty of these pharmacokinetic models.…”

Section: Future Researchmentioning

confidence: 99%

“…Recognizing the need to mitigate potential NPDI risk, the National Institutes of Health National Center for Complementary and Integrative Health established the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), which was tasked to develop a set of Recommended Approaches to guide optimal NPDI research studies. 12 These Recommended Approaches provide frameworks for the (i) selection and prioritization of NPs as precipitants of potential pharmacokinetic NPDIs 13 ; (ii) sourcing and characterization of NPs for in vitro and in vivo pharmacokinetic studies 14 ; and (iii) evaluation of an NP as a precipitant of pharmacokinetic NPDIs using predictive static and/or physiologically‐based pharmacokinetic (PBPK) models 15 (Figure 1 ). These predictive models are based on in vitro studies assessing the potential of an NP to inhibit or induce drug metabolizing enzymes (e.g., CYPs) or transporters (e.g., organic anion transporting polypeptides) at pharmacologically relevant unbound plasma or intestinal concentrations of the NP constituent(s).…”

Section: Introductionmentioning

confidence: 99%

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Adapting regulatory drug‐drug interaction guidance to design clinical pharmacokinetic natural product‐drug interaction studies: A NaPDI Center recommended approach

Cox

Rettie

Unadkat

et al. 2021

Clinical Translational Sci

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Pharmacokinetic drug interactions precipitated by botanical and other natural products (NPs) remain critically understudied. Investigating these complex interactions is fraught with difficulties due to the methodologic and technical challenges associated with the inherently complex chemistries and product variability of NPs. This knowledge gap is perpetuated by a continuing absence of a harmonized framework regarding the design of clinical pharmacokinetic studies of NPs and NP-drug interactions. Accordingly, this Recommended Approach, the fourth in a series of Recommended Approaches released by the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), provides recommendations for the design of clinical pharmacokinetic studies involving NPs. Building on prior Recommended Approaches and data generated from the NaPDI Center, such a framework is presented for the design of (1) phase 0 studies to assess the pharmacokinetics of an NP and (2) clinical pharmacokinetic NP-drug interaction studies. Suggestions for NP sourcing, dosing, study design, participant selection, sampling periods, and data analysis are presented. With the intent to begin addressing the gap between regulatory agencies' guidance documents about drug-drug interactions and contemporary NPDI research, the objective of this Recommended Approach is to propose methods for the design of clinical pharmacokinetic studies of NPs and NP-drug interactions.

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Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom

Tanna

Nguyen

Hadi

et al. 2023

Clin Pharma and Therapeutics

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Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid‐like effects to self‐manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50‐fold from 2011–2017, one‐third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom‐drug interactions. The impact of a single low dose of kratom tea (2 g) on the pharmacokinetics of the CYP3A probe midazolam (2.5 mg) and CYP2D6 probe dextromethorphan (30 mg) were assessed in 12 healthy adult participants after oral administration. Kratom showed no effect on dextromethorphan area under the plasma concentration time‐curve (AUC) and maximum concentration (Cmax; geometric mean ratio (90% confidence interval) 0.99 (0.83–1.19) and 0.96 (0.78–1.19), respectively) but a modest increase in midazolam AUC and Cmax (1.39 (1.23–1.57) and 1.50 (1.32–1.70), respectively). Lack of change in midazolam half‐life (1.07 (0.98–1.17)) suggested that kratom primarily inhibited intestinal CYP3A. This inference was further supported by a physiologically based pharmacokinetic drug interaction model using the abundant alkaloid mitragynine, a relatively potent CYP3A time‐dependent inhibitor in vitro (KI, ~4 μM; kinact, ~0.07 min−1). This work is the first to clinically evaluate the pharmacokinetic drug interaction potential of kratom. Co‐consuming kratom with certain drugs extensively metabolized by CYP3A may precipitate serious interactions. These data fill critical knowledge gaps about the safe use of this increasingly popular natural product, thereby addressing ongoing public health concerns.

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Modeling Pharmacokinetic Natural Product–Drug Interactions for Decision-Making: A NaPDI Center Recommended Approach

Cited by 8 publications

References 91 publications

Perspective on Improving the Relevance, Rigor, and Reproducibility of Botanical Clinical Trials: Lessons Learned From Turmeric Trials

Perspective on Improving the Relevance, Rigor, and Reproducibility of Botanical Clinical Trials: Lessons Learned From Turmeric Trials

Adapting regulatory drug‐drug interaction guidance to design clinical pharmacokinetic natural product‐drug interaction studies: A NaPDI Center recommended approach

Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom

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