Inter- and Intra-individual Variations in Metformin Pharmacokinetics - The Importance of Genes and Drug Interactions

Phase 1

Completed

• Conditions: Metformin; Organic Cation Transporter 1; Codeine
• Interventions: Drug: Oral metformin; Drug: Oral codeine and oral metformin; Drug: Oral codeine and intravenous metformin; Drug: Intravenous metformin

• Registration Number: NCT03335423
• Lead Sponsor: University of Southern Denmark

Brief Summary

The investigators aim to investigate the interindividual variation in metformin AUC in a large cohort of healthy volunteers after a single dose of metformin. Part 1 is driven by the hypothesis that metformin AUC and renal clearance exhibit significant interindividual variation. However this has never been documented in a large cohort of healthy volunteers.

The investigators aim to investigate the potential interaction between codeine and metformin in the intestine. The hypothesis underlying part 3 is that the increased risk of early discontinuation of metformin during co-administration with codeine is primarily due to local inhibition of OCT1 via codeine at the intestinal level.

Detailed Description

Part 1: The investigators intend to investigate the inter-individual variation in metformin Area Under Plasma Concentration Curve (AUC) following a single dose of oral metformin based on the plasma concentration of metformin after 3 and 10 hours and urine collection for 24 hours . Part 2: The investigators intend to contribute with DNA and metformin AUC determinations from subjects from part 1 to a major international study that aime to highlight the Genome Wide Association (GWA) between the entire genome and variations in metformin pharmacokinetics (AUC) in a large group of healthy subjects and patients. Part 3: The investigators aim to investigate the potential interaction between codeine and metformin in the intestine.

The investigators secondary objective in part 3 is to investigate if the plasma concentration of morphine increases when codeine and metformin are given together due to competitive inhibition of the Organic cation transporter 1 (OCT1) transport protein (in the liver). Furthermore, the investigators will measure lactate after metformin ingestion as a proxy for metformin's effect on the intestinal mucosa, both after oral and intravenous metformin

Study Timeline

• Study First Submitted: 2017-10-25
• Study First Submitted QC: 2017-11-03
• Study First Posted: 2017-11-07
• Status Verified: 2018-01
• Study Start: 2018-03-01
• Primary Completion: 2020-06-13
• Study Completion: 2020-06-13
• Last Update Submitted: 2020-06-24
• Last Update Posted: 2020-06-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 228

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Oral Metformin	Oral metformin	Oral metformin 1000mg will be given as a single dosis
Oral codeine and oral metformin	Oral codeine and oral metformin	Codeine 25 mg will be given at 5 occasions with approximately 6 hours between each dosing. The fifth and last dose will be given together with 1000 mg oral metformin
Oral codeine and intravenous metformin	Oral codeine and intravenous metformin	Codeine 25 mg will be given at 5 occasions with approximately 6 hours between each dosing. The fifth and last dose will be given together with 500 mg metformin administrated as an injection.
Intravenous metformin	Intravenous metformin	Intravenous metformin 500mg will be injected as a single dosis

Primary Outcome Measures

Name	Time	Method
Metformin AUC	Blood samples will be drawn in each of the 4 arms from ingestion of the drug/drugs and for 24 hours at suitable times. Urine is collected after ingestion of metformin for 24 hours.	Outcome of part 3; differences in AUC for metformin when given alone and together with codeine

Secondary Outcome Measures

Name	Time	Method
Codeine AUC	Blood samples are collected for 6 hours after ingestion of the first codeine pill. Blood samples are also collected and measured for codeine, morphing, M3G,M6G for 6 hours after both oral and intravenous metformin	secondary outcome of part 3: differences in codeine AUC when codeine is given alone and together with metformin
Lactate AUC	Blood samples for lactate will be drawn in each arm after metformin ingestion for 24 hours at suitable times	Secondary outcome of part 3: differences in lactate AUC after metformin is given orally and intravenously

Trial Locations

Locations (1)

The department of clinical pharmacy and pharmacology; 🇩🇰 Odense, Denmark