Impact of OCT1 and CYP2D6 Genotypes on Pharmacokinetics of Berberine in Healthy Volunteers (BERKI-1)

University Medicine Greifswald

Status: Completed

Conditions: Pharmacokinetic Study in Healthy Volunteers

Treatments: Dietary Supplement: Berberine

Study type: Interventional

Funder types: Other

Identifiers

NCT05463003

IPHA-2022-002

Details and patient eligibility

About

This study should investigate the differences of berberine pharmacokinetic parameters in three cohorts of healthy volunteers with distinct genotypes of the organic cation transporter 1 (OCT1) gene and the cytochrome P450 2D6 (CYP2D6) gene:

Cohort 1a) OCT1 and CYP2D6 wildtype genotypes n = 10 Cohort 1b) OCT1 and CYP2D6 wildtype genotypes n = 10 Cohort 2) OCT1 deficient/CYP2D6 wildtype genotypes n = 10 Cohort 3) OCT1 wildtype/CYP2D6 deficient genotypes n = 10 Participants will be selected from the study volunteers database of the Institute of Pharmacology in Greifswald according to their OCT1 and CYP2D6 genotypes and to achieve best matching according to sex, age, BMI, alcohol consumption and smoking between Cohort 1a and 2 or Cohort 1b and 3, respectively.

Full 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. A total of 12 blood samples will be taken at defined time points (baseline, 1; 1.5; 2; 3; 4; 5; 6; 8; 10; 24; 48 h). At each time point, blood will be collected in 2x 7.5 ml tubes for collecting serum and plasma samples to determine berberine, its metabolites and biomarkers of OCT1 transport and CYP2D6 enzymatic activity. At baseline, additional 2x 2.7 ml blood tubes will be collected for DNA isolation.

The total amount of blood collected for each participant is 190 ml at the three Pharmacokinetic Visits and 10 ml at the Screening Visit. Every hour, participants will drink 100 ml of sparkling water to stimulate intestinal peristalsis and promote transport of the capsule. After 2 hours, the participants may drink a cup of tea or coffee and after 4 hours they will be served a meal. Urine will be collected during the first 10 h after administration. Monitoring of vital parameters, e.g. blood pressure and heart rate, will take place for the first 4 hours after administration. The participants will stay in the Clinical Research Unit of the Institute of Pharmacology for the first 10 hours after administration.

Enrollment: 42 patients

Sex: All

Ages: 18 to 50 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• any sex
• OCT1 wildtype: homozygous for OCT*1
• OCT "poor transporter": homozygous or heterozygous for OCT1*3, *4, *5, *6
• CYP2D6 wildtype: homozygous or heterozygous for *1, *2, *35
• CYP2D6 "poor metabolizer": homozygous or heterozygous for *3, *4, *5, *6
• age between 18 and 50 years
• 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 orthopedic diseases
• a maximum of 3 chronically taken drugs not interfering with OCT1 and CYP2D6 activities

Exclusion criteria

• BMI > 35 kg/m2 and <18 kg/m2
• known pregnancy or lactation period
• women: positive urine pregnancy test at screening or pharmacokinetic visit
• anemia (hemoglobin < 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 and regularly draw blood through it

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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42 participants in 3 patient groups

OCT1 and CYP2D6 wildtype genotypes

Active Comparator group

Description:

In this group, the participants are OCT1 and CYP2D6 wildtype genotypes. The participants are selected to achieve best matching according to sex, age, BMI, alcohol consumption and smoking between arm (cohort) 1 and arm (cohort) 2 and 3, respectively.

Treatment:

Dietary Supplement: Berberine

OCT1 deficient and CYP2D6 wildtype genotypes

Active Comparator group

Description:

In this group, the participants are OCT1 deficient and CYP2D6 wildtype genotype.

Treatment:

Dietary Supplement: Berberine

OCT1 wildtype and CYP2D6 deficient genotypes

Active Comparator group

Description:

In this group, the participants are OCT1 wildtype and CYP2D6 deficient genotype.

Treatment:

Dietary Supplement: Berberine