Clinical trial NCT05157672: Evaluating the Pharmacokinetics and Drug Interaction Potential of the Botanical Dietary Supplement Cinnamon
Official title: Evaluating the Pharmacokinetics and Drug Interaction Potential of the Botanical Dietary Supplement Cinnamon
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: EARLY_PHASE1
Conditions: Interaction Drug Food
Keywords: pharmacokinetics
interaction
cinnamon
letrozole
nicotine
cinnamaldehyde
cinnamomum verum
natural product
Lead sponsor: Washington State University
Sponsor class: OTHER
Collaborators: name: National Center for Complementary and Integrative Health (NCCIH)
name: Office of Dietary Supplements (ODS)
First posted: 2021-12-15
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to evaluate a well-characterized, commercially available cinnamon dietary supplement as a precipitant of pharmacokinetic interactions with cytochrome P450 (CYP) 2A6 drug substrates in healthy volunteers. Nicotine gum will be used as the CYP2A6 probe drug (i.e., positive control) and letrozole as a high-impact object drug. Results will be used to inform future research on the potential use of cinnamon as a smoking cessation agent, as well as the clinical impact on pharmacotherapeutic regimens involving letrozole in cancer patients.

Detailed description: Cinnamon is used worldwide as both an additive and a botanical dietary supplement, the latter of which ranked within the 30 top-selling herbal supplements in 2020. Cinnamon is added to a variety of products, ranging from foods (e.g., breakfast cereals, baked goods) to fragrances and essential oils, to improve taste or smell. As a dietary supplement, cinnamon is commonly used to lower blood sugar and reduce inflammation. Cinnamon contains the abundant component, cinnamaldehyde (CA), a phenylpropanoid that emanates the flavor and scent of cinnamon. Research by Harrelson and colleagues has shown CA to inhibit the drug metabolizing enzyme cytochrome P450 (CYP) 2A6 in a time-dependent manner. That is, CYP2A6 metabolizes CA to a reactive intermediate that destroys the enzyme. Such substrates are also referred to as "suicide substrates". This type of enzyme inhibition is similar to that of grapefruit juice, which contains furanocoumarins that are time-dependent inhibitors of CYP3A in the intestine, leading to numerous potential adverse interactions with drugs metabolized by CYP3A. Unlike competitive inhibitors, time-dependent inhibitors inactivate the enzyme permanently, requiring de novo synthesis of the enzyme. As such, drug interactions with time-dependent inhibitors can last for several days. Relative to CYP3A, the list of clinically relevant CYP2A6 substrates is very short. However, two critical substrates include nicotine and the anticancer agent letrozole. Using an in vitro-to-in vivo extrapolation approach, CA was predicted to increase the area under the plasma concentration vs. time curve (AUC) of both substrates by 4- to 5-fold exceeding the FDA recommended cutoff (1.25) These compelling observations prompted this clinical study.

Eligibility criteria: Inclusion Criteria:

* Biological men and women, aged from 18-64 years and healthy
* Not taking any medications (prescription and non-prescription) or dietary/herbal supplements known to alter the pharmacokinetics of either study drug or cinnamon constituents
* Willing to abstain from consuming dietary/herbal supplements and citrus juices for several weeks
* Willing to abstain from consuming caffeinated beverages or other caffeine-containing products the evening before and morning of the first day of a study arm
* Willing to abstain from consuming any alcoholic beverages for one day prior to any study day, during the 14-hour inpatient days, and for the outpatient visit(s) following the 14-hour visit
* Willing to use an acceptable method of contraception that does not include oral contraceptive pills or patches (such as abstinence, copper IUD, condom)
* Have the time to participate
* Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for the subject to comply with the requirements of the study

Exclusion Criteria:

* Under the age of 18 or 65+ years
* Any current major illness or chronic illness such as (but not limited to) kidney disease, hepatic disease, diabetes mellitus, hypertension, coronary artery disease, chronic obstructive pulmonary disease, cancer, or HIV/AIDS
* History of anemia or any other significant hematologic disorder
* History of drug or alcohol addiction or major psychiatric illness
* Pregnant or nursing
* History of allergy to cinnamon, letrozole, or nicotine
* Taking concomitant medications, both prescription and non-prescription (including dietary supplements/herbal products), known to alter the pharmacokinetics of either study drug or cinnamon constituents
* Presence of a condition or abnormality that, in the opinion of the Investigator, would compromise the safety of the patient or the quality of the data
* Recreational drug use such as amphetamines, benzodiazepines, cocaine, marijuana, MDMA, opioids, and PCP
* History of intolerance to cinnamon
* Out-of-range clinical laboratory value that the study physician considers participation in the study a health risk

Primary outcomes:
measure: Nicotine area under the concentration vs. time curve (AUC) ratio (exposure/baseline)
timeFrame: 0-12 hours
Secondary outcomes:
measure: Cinnamon constituent area under the concentration vs. time curve (AUC)
timeFrame: 0-48 hours
measure: Cinnamon constituent maximum concentration (Cmax)
timeFrame: 0-48 hours
measure: Cinnamon constituent half-life
timeFrame: 0-48 hours
measure: Cinnamon renal clearance
timeFrame: 0-24 hours
measure: Letrozole area under the concentration vs. time curve (AUC) ratio (exposure/baseline)
timeFrame: 0-240 hours
measure: Nicotine and letrozole maximum concentration (Cmax) ratio (treatment/control)
timeFrame: 0-240 hours
measure: Nicotine and letrozole half-life ratio (treatment/control)
timeFrame: 0-240 hours
measure: Nicotine and letrozole renal clearance ratio (treatment/control)
timeFrame: 0-24 hours
Other outcomes:
Locations:
city: Spokane
country: United States
facility: Washington State University College of Pharmacy and Pharmaceutical Sciences
state: Washington
Study officials:
References:
citation: Smith T, Majid F, Eckl V, and Reynolds CM (2021) Herbal Supplement Sales in US Increase by Record-Breaking 17.3% in 2020. HerbalGram 131:52-65.
citation: Leach MJ, Kumar S. Cinnamon for diabetes mellitus. Cochrane Database Syst Rev. 2012 Sep 12;2012(9):CD007170. doi: 10.1002/14651858.CD007170.pub2.
citation: Chan J, Oshiro T, Thomas S, Higa A, Black S, Todorovic A, Elbarbry F, Harrelson JP. Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole. Drug Metab Dispos. 2016 Apr;44(4):534-43. doi: 10.1124/dmd.115.067942. Epub 2016 Feb 5.
citation: Espiritu MJ, Chen J, Yadav J, Larkin M, Pelletier RD, Chan JM, Gc JB, Natesan S, Harrelson JP. Mechanisms of Herb-Drug Interactions Involving Cinnamon and CYP2A6: Focus on Time-Dependent Inhibition by Cinnamaldehyde and 2-Methoxycinnamaldehyde. Drug Metab Dispos. 2020 Oct;48(10):1028-1043. doi: 10.1124/dmd.120.000087. Epub 2020 Aug 12.
citation: FDA (2020) Drug Interactions: Relevant Regulatory Guidance and Policy Documents
citation: Paine MF, Shen DD, McCune JS. Recommended Approaches for Pharmacokinetic Natural Product-Drug Interaction Research: a NaPDI Center Commentary. Drug Metab Dispos. 2018 Jul;46(7):1041-1045. doi: 10.1124/dmd.117.079962. Epub 2018 May 7.