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

NCT ID: NCT03335423

Last Updated: 2020-06-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 228 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-01
• Study Completion Date: 2020-06-13

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

Conditions

Metformin; Organic Cation Transporter 1; Codeine

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Oral Metformin

Oral metformin 1000mg will be given as a single dosis

Group Type: EXPERIMENTAL

Oral metformin

Intervention Type: DRUG

The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin

Intravenous metformin

Intravenous metformin 500mg will be injected as a single dosis

Group Type: EXPERIMENTAL

Intravenous metformin

Intervention Type: DRUG

The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous 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

Group Type: EXPERIMENTAL

Oral codeine and oral metformin

Intervention Type: DRUG

The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral 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.

Group Type: EXPERIMENTAL

Oral codeine and intravenous metformin

Intervention Type: DRUG

The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin

Interventions

Oral metformin

The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin

Intervention Type: DRUG

Intravenous metformin

The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin

Intervention Type: DRUG

Oral codeine and oral metformin

The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin

Intervention Type: DRUG

Oral codeine and intravenous metformin

The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

-

Exclusion Criteria

-

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Southern Denmark

OTHER

Sponsor Role: lead

Responsible Party

Ida Kuhlmann

Principal investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kim Brøsen, professor, chief physcian

Role: STUDY_CHAIR

University of Southern Denmark

Locations

The department of clinical pharmacy and pharmacology

Odense, , Denmark

Countries

Denmark

Other Identifiers

1779

Identifier Type: -

Identifier Source: org_study_id