Sex Differences in Berberine Pharmacokinetics (BERKI-2)

Sex Differences in Berberine Pharmacokinetics in Healthy Volunteers - BERKI-2

The influence of genetic variants of the CYP2D6 enzyme and the Organic Cation Transporter 1 on the kinetics of berberine (BERKI-1) has recently been studied. By chance, a significant sex difference was observed independent of the genetic variant. The Area under the curve of berberine in women compared to men was about three times higher, and the difference was statistically significant

The aim of BERKI-2 is to confirm the sex difference in an independent second study. In addition, influences of sex hormones on berberine kinetics in women will be studied.

As in BERKI-1, time-dependent blood and urine samples will be collected after a single berberine dose. By measuring berberine metabolites by Liquid Chromatography and Mass-spectrometry standard kinetic parameters e.g., AUC0-24, Cmax, Tmax will be calculated. Age-matched healthy women (n = 15) and men (n = 15) will be enroled.

Study Overview

• Status: Recruiting
• Conditions: Pharmacokinetic Study in Healthy Volunteers
• Intervention / Treatment: Dietary supplement: Berberine

Detailed Description

A single dose of 1000 mg berberine will be administered in two capsules with 250 ml of still water in the overnight fasting condition at 8 a.m.. A total of 11 blood samples will be taken at defined time points (baseline, 1; 1.5; 2; 3; 4; 5; 6; 8; 10; 24; h). At each time point, blood will be collected in 2x 7.5 ml tubes for collecting serum and plasma samples to determine berberine concentrations. Another serum sample will be obtained at baseline from women only to determine estradiol, progesterone, luteinizing hormone and follicle stimulating hormone to characterize the first and second phase of the cycle.

Every hour, participants will drink 100 ml of sparkling water to stimulate intestinal peristalsis and promote transport of the capsule. Volunteers are asked to stay in bed during the first four hours but are then allowed to move freely within the Clinical Research Unit. After 2 h, participants may drink a cup of tea or coffee and after 4 h they will be served a meal. Urine will be collected during the first 10 h after administration. Between 2 and 4 p.m., measuring body composition by bioelectrical impedance analysis (BIA) will be peformed to obtain fat mass and fat free mass (total and percentage) and body water. We use the seca mBCA 525 scale.The participants will stay in the Clinical Research Unit of the Institute of Pharmacology for the first 10 h after administration.

Women will undergo this treatment twice at least one week apart. Once in the first half (between days 4-10 after start of menstrual bleeding) and once in the second half (between days 20-26 after start of menstrual bleeding) of their menstrual cycle. The first day of menstrual bleeding marks day 1 as a reference.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Isabel Roth, Bachelor; Phone Number: +49 17692624200; Email: isabel.roth@med.uni-greifswald.de
• Study Contact Backup: Name: Stefan Engeli, Prof. Dr. med.; Phone Number: +49 3834865633; Email: Stefan.Engeli@med.uni-greifswald.de

Study Locations

• Germany
  • Mecklenburg-Vorpommern
    • Greifswald, Mecklenburg-Vorpommern, Germany, 17489
      • Recruiting
      • Center of Drug Absorption and Transport (C_DAT)
      • Contact: Stefan Engeli, Prof. Dr. med.; Phone Number: +49 3834865633; Email: Stefan.Engeli@med.uni-greifswald.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• wild type genotypes for CYP2D6 and Organic Cation Transporter 1
• understands the study purpose and design
• contractually capable and provides signed informed consent form
• healthy condition or mild and/or well treated forms of allergies, asthma, hypertension, and orthopaedic diseases
• no regular use of more than 2 drugs

Exclusion Criteria:

• volunteers who have already participated in BERKI-1
• BMI <18 kg/m2 and >35 kg/m2
• disorders of sex hormone regulation, hormone treatments
• women: menopause,known pregnancy or lactation period, positive urine pregnancy test at screening and at visits, oral contraceptives, depot contraceptives, or hormone-re-leasing intrauterine devices
• anaemia (haemoglobin < 13 g/dl (8,07 mmol/l) in men or < 12 g/dl (7,45 mmol/l) in women
• elevated liver function tests (> 2x ULN)
• reduced renal function (eGFRMDRD < 60 ml/min/1,7m2)
• psychiatric disease or drug dependency at time of visit
• use of recreational drugs more than twice a week
• poor venous conditions that make it impossible to place a peripheral venous catheter

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: woman; The participants are selected to achieve best matching according to sex, age, BMI, alcohol consumption and smoking between arm 1 and arm 2.	Dietary supplement: Berberine; A single dose of 1000 mg berberine in two capsules will be administered with 250 ml of still water in the overnight fasting condition. A total of 11 blood samples will be taken at defined time points (baseline, 1; 1.5; 2; 3; 4; 5; 6; 8; 10; 24 h). At each time point, blood will be collected in 2x 7.5 ml tubes for collecting serum and plasma samples to determine berberine concentrations. (Women will undergo the Intervention twice, once in the 1st half and once in the 2nd half of their menstrual cycle.) In addition urine will be collected over the time of 0-10 h after berberine intake and body composition will be measured by bioelectrical impedance analysis (BIA).
Active Comparator: men; The participants are selected to achieve best matching according to sex, age, BMI, alcohol consumption and smoking between arm 1 and arm 2.	Dietary supplement: Berberine; A single dose of 1000 mg berberine in two capsules will be administered with 250 ml of still water in the overnight fasting condition. A total of 11 blood samples will be taken at defined time points (baseline, 1; 1.5; 2; 3; 4; 5; 6; 8; 10; 24 h). At each time point, blood will be collected in 2x 7.5 ml tubes for collecting serum and plasma samples to determine berberine concentrations. (Women will undergo the Intervention twice, once in the 1st half and once in the 2nd half of their menstrual cycle.) In addition urine will be collected over the time of 0-10 h after berberine intake and body composition will be measured by bioelectrical impedance analysis (BIA).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Berberine plasma concentration women vs. men	Difference in berberine plasma concentrations expressed as Area under the Curve between women and men.	day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Berberine plasma concentrations durig first and second half of the menstrual cycle	Difference in berberine plasma concentrations expressed as Area under the Curve between the 1st and the 2nd phase of the female menstrual cycle.	day 1

Collaborators and Investigators

• Sponsor: University Medicine Greifswald

Study record dates

Study Major Dates

• Study Start (Actual): May 5, 2023
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): December 31, 2023

Study Registration Dates

• First Submitted: April 24, 2023
• First Submitted That Met QC Criteria: May 4, 2023
• First Posted (Actual): May 6, 2023

Study Record Updates

• Last Update Posted (Actual): June 5, 2023
• Last Update Submitted That Met QC Criteria: June 1, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: menstrual cycle; pharmacokinetic; Berberine; Sex differences
• Other Study ID Numbers: IPHA-2023-006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No