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

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ClinicalTrials.gov Identifier: NCT03335423
Recruitment Status : Completed
First Posted : November 7, 2017
Last Update Posted : June 25, 2020
Sponsor:
Information provided by (Responsible Party):
Ida Kuhlmann, 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.


Condition or disease Intervention/treatment Phase
Metformin Organic Cation Transporter 1 Codeine Drug: Oral metformin Drug: Intravenous metformin Drug: Oral codeine and oral metformin Drug: Oral codeine and intravenous metformin Phase 1

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 228 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

In part 1 a single group of healthy volunteers will ingest a single dosis of metformin and then have a blood sample drawn after 3 and 10 hours.

In part 3, 18 healthy subjects will be randomized to ingest: a) oral metformin b) intravenous metformin c) 4 pills of codeine with the 5th taken together with oral metformin and d) 4 pills of codeine with the 5th taken together with intravenous metformin.

Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Inter- and Intra-individual Variations in Metformin Pharmacokinetics - The Importance of Genes and Drug Interactions
Actual Study Start Date : March 1, 2018
Actual Primary Completion Date : June 13, 2020
Actual Study Completion Date : June 13, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Oral Metformin
Oral metformin 1000mg will be given as a single dosis
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

Experimental: Intravenous metformin
Intravenous metformin 500mg will be injected as a single dosis
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

Experimental: 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
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

Experimental: 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.
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




Primary Outcome Measures :
  1. Metformin AUC [ Time Frame: 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. ]
    Outcomes of part 1: Variation in metformin AUC in a large cohort of healthy volunteers after a single dose of metformin

  2. Metformin AUC [ Time Frame: 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 :
  1. Codeine AUC [ Time Frame: 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

  2. Lactate AUC [ Time Frame: 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03335423


Locations
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Denmark
The department of clinical pharmacy and pharmacology
Odense, Denmark, 5000
Sponsors and Collaborators
University of Southern Denmark
Investigators
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Study Chair: Kim Brøsen, professor, chief physcian University of Southern Denmark
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Responsible Party: Ida Kuhlmann, Principal investigator, University of Southern Denmark
ClinicalTrials.gov Identifier: NCT03335423    
Other Study ID Numbers: 1779
First Posted: November 7, 2017    Key Record Dates
Last Update Posted: June 25, 2020
Last Verified: January 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Metformin
Codeine
Hypoglycemic Agents
Physiological Effects of Drugs
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Antitussive Agents
Respiratory System Agents