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

NCT06122701 | Enrolling By Invitation

• 1 other identifier: IPHA-2023-007
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

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:

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

Conditions

Healthy

Keywords

Thiamin; Vitamin B1; OCT1; kinetic parameters; dose-dependency; genotypes

Outcome Measures

Primary Outcomes (1)

• Thiamin plasma concentrations expressed as Area under the Curve (AUC0-24 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

  24 hours

Secondary Outcomes (5)

• Cmax of thiamin and its phosphorylated esters, TMP and TDP

  24 hours

• Tmax of thiamin and its phosphorylated esters, TMP and TDP

  24 hours

• Total and renal clearance of thiamin and its phosphorylated esters, TMP and TDP

  24 hours

• Apparent volume of distribution of thiamin and its phosphorylated esters, TMP and TDP

  24 hours

• Plasma concentrations of known endogenous biomarkers such as isobutyrylcarnitine and propionylcarnitine

  24 hours

Study Arms (5)

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

ACTIVE COMPARATOR

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 p.o.

OCT1 deficient and wild type genotypes: 50 mg thiamin p.o.

ACTIVE COMPARATOR

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 p.o.

OCT1 deficient and wild type genotypes: 10 mg thiamin p.o.

ACTIVE COMPARATOR

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 p.o.

OCT1 deficient and wild type genotypes: 5 mg thiamin p.o.

ACTIVE COMPARATOR

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 p.o.

OCT1 deficient and wild type genotypes: 5 mg thiamin i.v.

ACTIVE COMPARATOR

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 i.v.

Interventions

Thiamin p.o. DIETARY_SUPPLEMENT

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.

OCT1 deficient and wild type genotypes: 10 mg thiamin p.o.; OCT1 deficient and wild type genotypes: 200 mg thiamin p.o.; OCT1 deficient and wild type genotypes: 5 mg thiamin p.o.; OCT1 deficient and wild type genotypes: 50 mg thiamin p.o.

Thiamin i.v. DIETARY_SUPPLEMENT

A single i.v. dose of thiamin 5 mg 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.

OCT1 deficient and wild type genotypes: 5 mg thiamin i.v.

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Medicine Greifswald: lead

Study Sites (1)

University Medicine Greifswald, Institute of Pharmacology

Greifswald, Mecklenburg-Vorpommern, 17489, Germany

Location

Study Officials

• Stefan Engeli

  Universitätsmedizin Greifswald, Institut für Pharmakologie

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: This study is an opel-label study.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med Stefan Engeli

Model Details: 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) and a single i.v. dose (5 mg).

Study Record Dates

• First Submitted: November 1, 2023
• First Posted: November 8, 2023
• Study Start: November 3, 2023
• Primary Completion: June 30, 2025
• Study Completion: August 31, 2025
• Last Updated: January 24, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)