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

Metformin Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03335423
• Other study ID #: 1779
• Status: Completed
• Phase: Phase 1
• Start date: March 1, 2018
• Est. completion date: June 13, 2020

Study information

• Verified date: January 2018
• Source: University of Southern Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 228
• Est. completion date: June 13, 2020
• Est. primary completion date: June 13, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria Part 1 (and 2): Men and women. Apparent good general health. eGFR, creatinine, Hba1c, must be within the reference range or clinically insignificantly differ from this. Written consent must be given. Age 18-65. BMI 18,5 - 29,9kg/m².

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Exclusion Criteria part 1 (and 2): Daily consumption of medicine (prescription, over the counter and herbal medicines, dietary supplements (oral contraceptives and regular vitamin pills are accepted)). Alcohol abuse. Hypersensitivity for metformin. For women: positive pregnancy test and not using safe contraceptives for 24 hours after intake of metformin and breastfeeding.

Inclusion Criteria Part 3:Apparent good general health. eGFR, creatinine, Hba1c, glucose, ALAT and bilirubin must be within the reference range or clinically insignificantly differ from this. Written consent must be given. Age 18-30 . BMI 18,5 - 29,9kg/m².

Exclusion Criteria part 3: Daily consumption of medicine (prescription, over the counter and herbal medicines, dietary supplements (regular vitamin pills are accepted)). Alcohol abuse. Hypersensitivity for metformin, codeine or morphine. Genetically proven CYP2D6 slow or ultra-fast metabolizers. Genetically proven loss-of-function allele in OCT1

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Related Conditions & MeSH terms

• Codeine
• Metformin
• Organic Cation Transporter 1

Intervention

Drug:
• 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
• 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
• 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
• 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

Locations

Country	Name	City	State
Denmark	The department of clinical pharmacy and pharmacology	Odense

Sponsors (1)

Lead Sponsor	Collaborator
University of Southern Denmark

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Metformin AUC	Outcomes of part 1: Variation in metformin AUC in a large cohort of healthy volunteers after a single dose of metformin	blood samples will be collected after 3 and 10 hours for each subject (N=300) after oral metformin ingestion. Urine is collected for 24 hours.
Primary	Metformin AUC	Outcome of part 3; differences in AUC for metformin when given alone and together with codeine	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.
Secondary	Codeine AUC	secondary outcome of part 3: differences in codeine AUC when codeine is given alone and together with metformin	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	Lactate AUC	Secondary outcome of part 3: differences in lactate AUC after metformin is given orally and intravenously	Blood samples for lactate will be drawn in each arm after metformin ingestion for 24 hours at suitable times