Dose-dependent Kinetics of Thiamin in Healthy Volunteers with and Without Functional OCT1 Hepatic Transporters (THIAMO-1)

University Medicine Greifswald

Status

Invitation-only

Conditions

Healthy

Treatments

Dietary Supplement: Thiamin p.o.

Dietary Supplement: Thiamin i.v.

Study type

Interventional

Funder types

Other

Identifiers

NCT06122701

IPHA-2023-007

Details and patient eligibility

About

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.

Full description

The study is designed as a 5-arm cross-over, open-label, randomized single oral dose comparison (5 mg, 10 mg, 50 mg, and 200 mg thiamin). A fifth arm includes applying 5 mg thiamin intravenously.

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 decided to administer a single i.v. dose of 5 mg thiamin in arm 5.

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.

Enrollment

36 estimated patients

Sex

All

Ages

18 to 50 years old

Volunteers

Accepts Healthy Volunteers

Inclusion criteria

any sex
age between 18 and 50 years
OCT1 wild type: homozygous for OCT1*1 OCT "poor transporter": homozygous or heterozygous for OCT1*3, *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

Trial design

Primary purpose

Basic Science

Allocation

Randomized

Interventional model

Crossover Assignment

Masking

None (Open label)

36 participants in 5 patient groups

OCT1 deficient and wild type genotypes: 200 mg thiamin p.o.

Active Comparator group

Description: