Clinical trial NCT05463003: Impact of OCT1 and CYP2D6 Genotypes on Pharmacokinetics of Berberine in Healthy Volunteers
Official title: Impact of OCT1 and CYP2D6 Genotypes on Pharmacokinetics of Berberine in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Pharmacokinetic Study in Healthy Volunteers
Keywords: Berberine
OCT1
CYP2D6
pharmacogenetic
pharmacokinetic
Lead sponsor: University Medicine Greifswald
Sponsor class: OTHER
First posted: 2022-07-18
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study should investigate the differences of berberine pharmacokinetic parameters in three cohorts of healthy volunteers:

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
Primary purpose: TREATMENT

Brief summary: 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.

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. 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.

Eligibility criteria: 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

Primary outcomes:
measure: Berberine plasma and serum concentration expressed as Area under the Curve (AUC0-48 hours).
timeFrame: 48 hours
Secondary outcomes:
measure: Highest concentration (Cmax) of berberine and the berberine metabolites M1-M9.
timeFrame: 48 hours
measure: Time point of highest concentration (Tmax) of berberine and the berberine metabolites M1-M9.
timeFrame: 48 hours
measure: Clearance of berberine and the berberine metabolites M1-M9.
timeFrame: 48 hours
measure: Apparent volume of distribution of berberine and the berberine metabolites M1-M9.
timeFrame: 48 hours
measure: Changes of plasma concentrations of known endogenous biomarkers like isobutyrylcarnitine
timeFrame: 48 hours
Other outcomes:
Locations:
city: Greifswald
country: Germany
facility: University Medicine Greifswald, Institute of Pharmacology
state: Mecklenburg-Vorpommern
Study officials:
affiliation: Universitätsmedizin Greifswald, Institut für Pharmakologie
name: Stefan Engeli, Prof.
role: PRINCIPAL_INVESTIGATOR
References: