Clinical trial NCT04932265: Effect of Gamma-cyclodextrin on the Bioavailability of Ginsenosides
Official title: Dissolution and Pharmacokinetic of Ginsenosides Released From Cyclodextrin Based Chewable Tablets: a Comparative, Randomized, Crossover, Open-label Study in Healthy Human Subjects.
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE1
Conditions: Drug Absorption
Keywords: Ginsenosides Rg5
Ginsenosides Rk1
Compound K (CK).
Red ginseng HRG80
gamma-cyclodextrin
pharmacokinetic
relative bioavailability
Lead sponsor: EuroPharma, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Phytomed AB, Sweden
name: Scientific Center of Drug and Medical Technologies Expertise of the Ministry of Health, Armenia
name: CARDIOMED Family Health Center, LLC of the Ministry of Health of Armenia
name: Institute of Fine Organic Chemistry of the National Academy of Science Yerevan, Armenia
First posted: 2021-06-21
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: A comparative study with the positive control, parallel groups, randomized, crossover design
Primary purpose: TREATMENT

Brief summary: This study will evaluate the relative bioavailability of ginsenosides Rg5, Rk1, and Ck of Red ginseng HRG80 preparations containing gamma-cyclodextrin (GCD) in the blood plasma of healthy subjects after oral administration of two different formulations of HRG80:

A. Capsules containing red ginseng preparation HRG80 (reference product) B. Chewable tablets containing red ginseng preparation HRG80 and GCD (modified product).

Dissolution testing measures the rate and extend water solubility of ginsenosides from the reference (A) and the modified (B) products. The difference of in vitro dissolution profiles between the reference (A) and modified (B) products will be assessed.

Detailed description: A growing body of evidence suggests that gamma-cyclodextrin (GCD) can increase the clinical efficacy of water-insoluble biologically active compounds, which have low bioavailability. GCD is the most bio adaptable and applicable to increase the absorption of many drugs, including ginsenosides of Panax ginseng, by forming inclusion complexes or the form of GCD/drug conjugates. Ginsenosides have absolute bioavailability in the range from 0.2% to 48%, depending on the chemical structure and water solubility.

Hypothesis: gamma-cyclodextrin increases absorption and bioavailability of active constituents - Ginsenosides Rg5, Rk1, and Compound K (CK). The study aims to provide experimental evidence supporting or rejecting this hypothesis.

Sixteen healthy volunteers will be randomly assigned to receive two formulations, A and B, in two consecutive phases (Phase 1 and Phase) of an open-label study with a crossover design.

All patients will provide blood samples in each phase in each phase in 0.5, 0.75, 1, 2, 4, 6, 12, 24, and 48 hours (9 points) after drug administration, following will be a washout period for two weeks.

Subjects will be fasting for 10.00 hours before administering the investigational product. They will remain in the clinic post-dose until at least 24.00 hours each period, provided they are not suffering from any adverse event.

The concentration of ginsenosides Rg5, Rk1, and Ck in all blood samples will be determined using a validated analytical method (HPLC-MS) with the internal standard - digoxin. Appropriate mathematical methods and Kinetic 4.4.1 software will be used to generate basic pharmacokinetic parameters.

Eligibility criteria: Inclusion Criteria:

* Healthy volunteers, as determined by medical history, physical examination, and clinical laboratory testing,
* Willingness to stay in the unit overnight for the duration of the study,
* Provide a signed written informed consent.

Exclusion Criteria:

* overweight (BMI \>35 kg/m2),
* pregnancy,
* lactation,
* drug abuse,
* use of dietary supplements or any form of medication (with the exception of oral contraceptives),
* heavy smokers, or ex-smokers with a remote history (\> one pack/day),
* frequent alcohol consumption (\>20 g ethanol/d),
* adherence to a restrictive dietary regimen,
* physical activity of more than 5 h/wk,
* respiratory tract infections, or suspicion thereof in the last 14 days before dosing,
* history or presence of disease in the kidneys and heart, lungs, liver, the gastrointestinal tract, endocrine organs, or other conditions such as the metabolic disease is known to interfere with the absorption, distribution, metabolism, and excretion of drugs,
* malignancy,
* autoimmune disorders such as (but not limited to) lupus erythematosus, multiple sclerosis, rheumatoid arthritis, or sarcoidosis,
* any other disease or condition, which, in the opinion of the Investigator, would make the subject unsuitable for this study,
* currently taking medications known to be CYP2C9 inducers (i.e., carbamazepine and rifampicin).

Primary outcomes:
measure: The area under the plasma concentration versus time curve (AUC, expressed in ng x h/mL) of Rg5.
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: The area under the plasma concentration versus time curve (AUC, expressed in ng x h/mL) of Rk1.
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: The area under the plasma concentration versus time curve (AUC, expressed in ng x h/mL) of ginsenoside Ck
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
Secondary outcomes:
measure: The absorption rate constant (Ka, h-1) of Rg5
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: The absorption rate constant (Ka, h-1) of Rk1
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: The absorption rate constant (Ka, h-1) of Ck
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Maximum plasma concentration (Cmax, ng/ml), of Rg5
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Maximum plasma concentration (Cmax, ng/ml), of Rk1
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Maximum plasma concentration (Cmax, ng/ml), of Ck
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Time to reach maximum plasma concentration, Tmax (h) of Rg5 .
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Time to reach maximum plasma concentration, Tmax (h) of Rk1
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Time to reach maximum plasma concentration, Tmax (h) of Ck.
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Mean absorption time MAT (h) of Rg5
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Mean absorption time MAT (h) of Rk1
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Mean absorption time MAT (h) of Ck
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
Other outcomes:
measure: Relative bioavailability (%) of Rg5 incorporated in gamma-cyclodextrin
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Relative bioavailability (%) of Rk1 incorporated in gamma-cyclodextrin
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Relative bioavailability (%) of Ck incorporated in gamma-cyclodextrin
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Effect of gamma-cyclodextrin on absorption rate constant (Ka, h-1) of Rg5
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Effect of gamma-cyclodextrin on absorption rate constant (Ka, h-1) of Rk1
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Effect of gamma-cyclodextrin on absorption rate constant (Ka, h-1) of Ck
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Effect of gamma-cyclodextrin on the maximal concentration (ng/ml) of Rg5 in blood
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Effect of gamma-cyclodextrin on the maximal concentration (ng/ml) of Rk1 in blood
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: Effect of gamma-cyclodextrin on the maximal concentration (ng/ml) of Ck in blood
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: the dissolution of Rg5
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: the dissolution of Rk1
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
measure: the dissolution of Ck
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
Locations:
city: Yerevan
country: Armenia
facility: CARDIOMED Family Health Center, LLC of the Ministry of Health of the Republic of Armenia
city: Yerevan
country: Armenia
facility: Institute of Fine Organic Chemistry of the National Academy of Science
city: Yerevan
country: Armenia
facility: Scientific Center of Drug and Medical Technologies Expertise
city: Vaxtorp
country: Sweden
facility: Phytomed AB
state: HL
Study officials:
affiliation: Scientific Center of Drug and Medical Technologies Expertise of the Ministry of Health of the Republic of Armenia
name: Aghavni T Ginosyan, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CARDIOMED Family Health Center, LLC of the Ministry of Health of the Republic of Armenia
name: Samvel Hairumyan, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Institute of Fine Organic Chemistry of the National Academy of Science, Armenia
name: Areg Hovhannisyan PhD of A Hovhannisyan
role: STUDY_DIRECTOR
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