THIAMO-1: Dose-dependent Kinetics of Thiamin in Healthy Volunteers With and Without Functional OCT1 Hepatic Transporters

Sponsor

University Medicine Greifswald (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06122701

Collaborator

(none)

Enrollment

Location

Arms

12.4

Anticipated Duration (Months)

1.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study investigates the differences in thiamin (vitamin B1) kinetic parameters in two cohorts of healthy volunteers:

Cohort 1) OCT1 wild type genotypes n = 12 Cohort 2) OCT1 deficient genotypes n = 12 Participants will be selected according to their OCT1 genotypes and to achieve best matching according to sex, age, BMI, alcohol consumption, and smoking between Cohort 1 and 2, respectively.

The purpose of this study is:

To determine the influence of OCT1 genetic variants on dose-dependent thiamin kinetics after oral administration.
To elucidate whether OCT1 genetic variants impact the kinetic properties of orally vs. intravenously administered thiamin.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Dietary Supplement: Thiamin	N/A

Detailed Description

A single oral dose of thiamin will be administered in four intervention arms (arm 1: 200 mg, arm 2: 50 mg, arm 3: 10 mg, arm 4: 5 mg) as a drinking solution with 240 ml of still water after an overnight fast. These four arms will be put into practice at the same time with each participant completing all four arms in random order with a wash-out period of at least one week between each arm.

After analyzing the four oral arms, we will administer a single i.v. dose of thiamin in arm 5 at a later time point. The dosage will be determined after analyzing the results of orally administered thiamin in arm 2 to 4.

A total of 15 blood samples will be taken at defined time points (baseline; 0.25; 0.5; 0.75; 1.0; 1.5; 2.0; 2.5; 3.0; 3.5; 4.0; 6.0; 8.0; 10.0; 24.0 h). At each time point, blood will be collected (4.9 ml for plasma and 2.7 ml for whole blood) to determine thiamin, TMP and TDP, and biomarkers of OCT1 transport activity. At baseline, 2x 2.7 ml EDTA blood samples will be collected for DNA isolation if the particular volunteer has not had a genotypical validation in another study of our Institute.

The total amount of blood collected for each participant is 456 ml at eight kinetic visits and 10 ml at the Screening.

After intake of the thiamin solution, participants will drink 100 ml of sparkling water every hour to stimulate gastrointestinal peristalsis. After 4 hours the participants will be served a meal low in thiamin content. Urine will be collected during the first 10 hours after thiamin administration. Monitoring of blood pressure and heart rate will take place for the first 4 hours after administration. Volunteers will stay in the Clinical Research Unit of the Institute of Pharmacology for the first 10 hours after administration.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

24 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

The study is designed as a 4-arm cross-over, open-label, randomized single oral dose comparison (5 mg, 10 mg, 50 mg, and 200 mg thiamin). A fifth arm applying thiamin intravenously with a dose selected based on results from the four oral arms is also planned.The study is designed as a 4-arm cross-over, open-label, randomized single oral dose comparison (5 mg, 10 mg, 50 mg, and 200 mg thiamin). A fifth arm applying thiamin intravenously with a dose selected based on results from the four oral arms is also planned.

Masking:

None (Open Label)

Masking Description:

This study is an opel-label study.

Primary Purpose:

Basic Science

Official Title:

Cross-over Randomized Study to Determine Dose-dependent Kinetics of Thiamin in Healthy Volunteers With and Without Functional OCT1 Hepatic Transporters

Anticipated Study Start Date :

Nov 20, 2023

Anticipated Primary Completion Date :

Dec 1, 2024

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: OCT1 deficient and wild type genotypes: 200 mg thiamin The participants are selected to achieve best matching according to sex, age, BMI, alcohol consumption and smoking between cohort 1 and cohort 2.	Dietary Supplement: Thiamin A single oral dose of thiamin will be administered in four intervention arms (arm 1: 200 mg, arm 2: 50 mg, arm 3: 10 mg, arm 4: 5 mg) as a drinking solution with 240 ml of still water after an overnight fast. A total of 15 blood samples will be taken at defined time points (baseline; 0.25; 0.5; 0.75; 1.0; 1.5; 2.0; 2.5; 3.0; 3.5; 4.0; 6.0; 8.0; 10.0; 24.0 h). At each time point, blood will be collected (4.9 ml for plasma and 2.7 ml for whole blood) to determine thiamin, TMP and TDP, and biomarkers of OCT1 transport activity. Urine will be collected during the first 10 hours after thiamin administration.
Active Comparator: OCT1 deficient and wild type genotypes: 50 mg thiamin The participants are selected to achieve best matching according to sex, age, BMI, alcohol consumption and smoking between cohort 1 and cohort 2.	Dietary Supplement: Thiamin A single oral dose of thiamin will be administered in four intervention arms (arm 1: 200 mg, arm 2: 50 mg, arm 3: 10 mg, arm 4: 5 mg) as a drinking solution with 240 ml of still water after an overnight fast. A total of 15 blood samples will be taken at defined time points (baseline; 0.25; 0.5; 0.75; 1.0; 1.5; 2.0; 2.5; 3.0; 3.5; 4.0; 6.0; 8.0; 10.0; 24.0 h). At each time point, blood will be collected (4.9 ml for plasma and 2.7 ml for whole blood) to determine thiamin, TMP and TDP, and biomarkers of OCT1 transport activity. Urine will be collected during the first 10 hours after thiamin administration.
Active Comparator: OCT1 deficient and wild type genotypes: 10 mg thiamin The participants are selected to achieve best matching according to sex, age, BMI, alcohol consumption and smoking between cohort 1 and cohort 2.	Dietary Supplement: Thiamin A single oral dose of thiamin will be administered in four intervention arms (arm 1: 200 mg, arm 2: 50 mg, arm 3: 10 mg, arm 4: 5 mg) as a drinking solution with 240 ml of still water after an overnight fast. A total of 15 blood samples will be taken at defined time points (baseline; 0.25; 0.5; 0.75; 1.0; 1.5; 2.0; 2.5; 3.0; 3.5; 4.0; 6.0; 8.0; 10.0; 24.0 h). At each time point, blood will be collected (4.9 ml for plasma and 2.7 ml for whole blood) to determine thiamin, TMP and TDP, and biomarkers of OCT1 transport activity. Urine will be collected during the first 10 hours after thiamin administration.
Active Comparator: OCT1 deficient and wild type genotypes: 5 mg thiamin The participants are selected to achieve best matching according to sex, age, BMI, alcohol consumption and smoking between cohort 1 and cohort 2.	Dietary Supplement: Thiamin A single oral dose of thiamin will be administered in four intervention arms (arm 1: 200 mg, arm 2: 50 mg, arm 3: 10 mg, arm 4: 5 mg) as a drinking solution with 240 ml of still water after an overnight fast. A total of 15 blood samples will be taken at defined time points (baseline; 0.25; 0.5; 0.75; 1.0; 1.5; 2.0; 2.5; 3.0; 3.5; 4.0; 6.0; 8.0; 10.0; 24.0 h). At each time point, blood will be collected (4.9 ml for plasma and 2.7 ml for whole blood) to determine thiamin, TMP and TDP, and biomarkers of OCT1 transport activity. Urine will be collected during the first 10 hours after thiamin administration.

Outcome Measures

Primary Outcome Measures

Thiamin whole blood concentrations expressed as Area under the Curve (AUC0-24 hours) [24 hours]
Difference in thiamin whole blood concentrations expressed as Area under the Curve (AUC0-24 hours) between OCT1 wild type and OCT1 deficiency cohorts (Cohort 1 vs. Cohort 2) in each dose arm

Secondary Outcome Measures

Thiamin plasma concentrations expressed as Area under the Curve (AUC0-24 hours) [24 hours]
Difference in thiamin plasma concentrations expressed as Area under the Curve (AUC0-24 hours) between OCT1 wild type and OCT1 deficiency cohorts (Cohort 1 vs. Cohort 2) in each dose arm
Cmax of thiamin and its phosphorylated esters, TMP and TDP [24 hours]
Differences in Cmax of thiamin and its phosphorylated esters, TMP and TDP, between the above-described cohorts in each dose arm
Tmax of thiamin and its phosphorylated esters, TMP and TDP [24 hours]
Differences in Tmax of thiamin and its phosphorylated esters, TMP and TDP, between the above-described cohorts in each dose arm
Total and renal clearance of thiamin and its phosphorylated esters, TMP and TDP [24 hours]
Differences in total and renal clearance of thiamin and its phosphorylated esters, TMP and TDP, between the above-described cohorts in each dose arm
Apparent volume of distribution of thiamin and its phosphorylated esters, TMP and TDP [24 hours]
Differences in the apparent volume of distribution of thiamin and its phosphorylated esters, TMP and TDP, between the above-described cohorts in each dose arm
Plasma concentrations of known endogenous biomarkers such as isobutyrylcarnitine and propionylcarnitine [24 hours]
Changes in plasma concentrations of known endogenous biomarkers such as isobutyrylcarnitine and propionylcarnitine measured at all time points following thiamin administration

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

any sex
age between 18 and 50 years
OCT1 wild type: homozygous for OCT11 OCT "poor transporter": homozygous or heterozygous for OCT13, *4, *5, *6
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 activity

Exclusion Criteria:

BMI > 32 kg/m2 and < 17 kg/m2
body weight < 48 kg
known pregnancy or lactation period
women: positive urine pregnancy test at screening or kinetic visit 1 of each arm
men: hemoglobin < 13 g/dl (8,07 mmol/l) women: hemoglobin < 12 g/dl (7,45 mmol/l)
elevated liver function tests (1 or more of ALAT, ASAT, yGT, Bilirubin > 2x ULN)
reduced renal function (eGFRMDRD < 60 ml/min/1,7 m2)
QTcF > 450 ms in screening ECG
psychiatric disease requiring recent or actual treatment
drug dependency at the time of visit
use of recreational drugs more than twice a week
any known hypersensitivity or allergic reactions to thiamin
history of severe hypersensitivity reactions and/or anaphylaxis
clinically proven vitamin B1 deficiency
individuals taking regular vitamin B1 or multi-vitamin supplements who are not willing to comply with a 48-hour washout of these supplements before each kinetic visit
individuals who have taken vitamin B supplements or multi-vitamins in the past 2 days before kinetic visit 1 of each arm
poor venous conditions that make it impossible to place a peripheral venous catheter and regularly draw blood through it