The Effect of SLC19A3 Inhibition on the Pharmacokinetics of Thiamine

In Part 1, subjects will be administered thiamine, thiamine with metformin, and thiamine with trimethoprim. Part 2 will expand on Part 1 and subjects will be administered thiamine and thiamine with trimethoprim. The goal is to determine whether taking a drug and a vitamin together affects the body's ability to absorb, distribute, and eliminate thiamine (Vitamin B1).

Study Overview

• Status: Completed
• Conditions: Vitamin B1 Deficiency; Thiamine Deficiency
• Intervention / Treatment: Dietary supplement: Vitamin B1; Drug: Trimethoprim; Drug: Metformin

Detailed Description

Thiamine is an essential vitamin meaning humans must consume thiamine from their diet in order to stay healthy. Low thiamine levels can lead to adverse events. Thiamine is absorbed in the intestine by a transporter protein. This is made by the SLC19A3 gene. The SLC19A3 gene provides instructions for making the thiamine transporter protein, which moves thiamine into cells. Certain drugs, like metformin and trimethoprim, have been shown to interrupt function of the SLC19A3 gene.

Metformin is a first-line therapy for patients with Type 2 diabetes and is associated with improvements in diabetic complications. Trimethoprim is an anti-bacterial drug that is often prescribed to treat infections such as urinary tract infections. At different phases of this study, participants will be administered thiamine, thiamine with metformin, and/or thiamine with trimethoprim to determine whether taking a drug and a vitamin together affects the body's ability to absorb, distribute, and eliminate thiamine. The levels of thiamine in the participants' blood and urine will be measured before and after taking thiamine or thiamine in combination with metformin and/or trimethoprim.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Andrew S Greenberg; Phone Number: 617-556-3144; Email: Andrew.greenberg@tufts.edu
• Study Contact Backup: Name: Kim T Trinh; Phone Number: 617-556-3320; Email: ktrinh01@exchange.tufts.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Jean Mayer USDA Human Nutrition Research Center on Aging

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Male or female between the ages of 18-65 years old.
2. Eats a wide variety of food and willing to consume study diet (i.e. not on a specific diet such as Atkins, Fodmap, etc.).
3. Written informed consent obtained from the subject and ability for subject to comply with the requirements of the study.

Exclusion Criteria:

1. Subjects who are pregnant, breastfeeding, or unwilling to practice birth control during participation in the study.
2. Self-reported severe food allergies or diet restrictions (vegans, vegetarians, Atkins, Fodmap, etc.) that would prevent consumption of study diets.
3. Subjects with extreme obesity (BMI > 35).
4. Subjects who are smokers or have smoked in the past year and/or have smoked or ingested THC/marijuana in the past week, or who are unwilling to comply with a 1-week washout.
5. Subjects with any disease affecting or impairing the function of the liver, kidney or heart.
6. Subjects with moderate to severe hypertension.
7. Subjects with diabetes mellitus, hyperthyroidism, hypothyroidism, cardiovascular disease, glaucoma.
8. Subjects with gastrointestinal disease, gastrointestinal disorder, or gastrointestinal surgery.
9. Subjects with known infection with HIV, Hepatitis B (HBsAg) or Hepatitis C (no laboratory diagnostics concerning these diseases will be performed within the present study. Volunteers who are cured of past HepC infection are eligible to participate with doctor's approval letter).
10. Alcohol use on average > 2 servings/day or > 14 servings/wk (Serving size: 12oz beer/4oz wine/2oz hard liquor) or self-reported binge drinking.
11. Subjects that are on vitamin B supplements or multi-vitamins or who have taken vitamin B supplements or multi-vitamins in the past 30 days, or are not willing to comply with a 30-day washout of vitamin B supplements.
12. Subjects with possible folate deficiency.
13. Subjects taking any other clinically significant drugs as judged by the investigator.
14. Subjects with a condition, disease, or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
15. Female subjects undergoing treatment for infertility or hormone replacement therapy (Volunteers using hormonal birth control will not be excluded).
16. Subjects who have taken antimalarials in the past 60 days.
17. Participating in another research study while participating in this research study.
18. Non-English speaking
19. Subjects with abnormal laboratory results at screening as judged by the investigator or study physician.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Thiamine only; 5mg thiamine tablet by mouth. This arm will be included in both Parts 1 and 2 of the study.	Dietary supplement: Vitamin B1; 5mg of thiamine will be given alone and in combination for both Parts 1 and 2 of the study.; Other Names: Thiamine
Experimental: Trimethporim + thiamine combination; 5mg thiamine tablet and 300mg trimethoprim tablet by mouth. This arm will be included in both Parts 1 and 2 of the study.	Dietary supplement: Vitamin B1; 5mg of thiamine will be given alone and in combination for both Parts 1 and 2 of the study.; Other Names: Thiamine; Drug: Trimethoprim; 300mg of trimethoprim will be given in combination with 5mg thiamine and compared to 5mg thiamine only for both Parts 1 and 2 of the study.; Other Names: Primsol
Experimental: Metformin + thiamine combination; 5mg thiamine tablet and 1000mg metformin tablet by mouth. This arm will be included in only Part 1 of the study.	Dietary supplement: Vitamin B1; 5mg of thiamine will be given alone and in combination for both Parts 1 and 2 of the study.; Other Names: Thiamine; Drug: Metformin; 1000mg of metformin will be given in combination with 5mg thiamine and compared to 5mg thiamine only in Part 1 of the study.; Other Names: Glucophage

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration-Time Curve (AUC 0-72h)	Blood samples were obtained and plasma concentrations were determined using a validated high-pressure liquid chromatography method.	As determined by blood/urine levels taken over the course of 2-3 cycles (each cycle is 3 days with a 5-14 day washout in between cycles)
Assess the effects of SLC19A3 inhibitors by Cmax	In Parts 1 and 2, assess the effects of SLC19A3 inhibitors on the absorption and distribution of thiamine as measured by the change in maximum concentration (Cmax) between the combination arm(s) and single agent arm.	As determined by blood/urine levels taken over the course of 2-3 cycles (each cycle is 3 days with a 5-14 day washout in between cycles)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Investigate metabolic signatures reflecting the activity of TPP-dependent enzymes	In Parts 1 and 2, investigate metabolic signatures reflecting the activity of TPP-dependent enzymes after the administration of thiamine or a combination of the thiamine and SLC19A3 inhibitor. Metabolic signatures are measured in blood samples by LC-MS (measurement tool). The units of measure are relative abundance, which is expressed as a percentage of the total metabolites detected.	As determined by blood/urine levels taken over the course of 2-3 cycles (each cycle is 3 days with a 5-14 day washout in between cycles)
Determine the effect of genetic variants of thiamine transporters	The investigators will use Sanger Sequencing of two thiamine transporters (SLC19A2 and SLC19A3) to identify genetic variants in DNA extracted from blood samples. Sanger sequencing is done by Polymerase Chain Reaction (PCR) instrumentation and the unit of measure is single nucleotide polymorphism (SNPs) detected.	As determined by blood/urine levels taken over the course of 2-3 cycles (each cycle is 3 days with a 5-14 day washout in between cycles)]

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Tufts University; University of California, Davis
• Investigators: Principal Investigator: Kathleen M Giacomini, University of California, San Francisco; Principal Investigator: Andrew S Greenberg, Tufts University

Study record dates

Study Major Dates

• Study Start (Actual): January 28, 2019
• Primary Completion (Actual): August 10, 2023
• Study Completion (Actual): August 10, 2023

Study Registration Dates

• First Submitted: November 8, 2018
• First Submitted That Met QC Criteria: November 14, 2018
• First Posted (Actual): November 19, 2018

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 10, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Drug-induced vitamin deficiency
• Additional Relevant MeSH Terms: Nutrition Disorders; Avitaminosis; Deficiency Diseases; Malnutrition; Vitamin B Deficiency; Thiamine Deficiency; Beriberi; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Micronutrients; Cytochrome P-450 Enzyme Inhibitors; Vitamins; Antiprotozoal Agents; Antiparasitic Agents; Vitamin B Complex; Antimalarials; Folic Acid Antagonists; Anti-Dyskinesia Agents; Anti-Infective Agents, Urinary; Cytochrome P-450 CYP2C8 Inhibitors; Metformin; Trimethoprim; Thiamine
• Other Study ID Numbers: 13060; 5R01DK108722-02 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes