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

NCT03335423 | Completed Phase 1

• 1 other identifier: 1779
• Study Type: interventional
• Target: 228
• Locations: 1 country
• Sites: 1

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.

Conditions

Metformin; Organic Cation Transporter 1; Codeine

Outcome Measures

Primary Outcomes (2)

• 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.

• 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 Outcomes (2)

• 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

• Lactate AUC

  Blood samples for lactate will be drawn in each arm after metformin ingestion for 24 hours at suitable times

Study Arms (4)

Oral Metformin

EXPERIMENTAL

Oral metformin 1000mg will be given as a single dosis

Drug: Oral metformin

Intravenous metformin

EXPERIMENTAL

Intravenous metformin 500mg will be injected as a single dosis

Drug: Intravenous metformin

Oral codeine and oral metformin

EXPERIMENTAL

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

Oral codeine and intravenous metformin

EXPERIMENTAL

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

Interventions

Oral metformin 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 Metformin

Intravenous metformin 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

Oral codeine and oral metformin 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

Oral codeine and intravenous metformin 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

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

Sponsors & Collaborators

• University of Southern Denmark: lead

Study Sites (1)

The department of clinical pharmacy and pharmacology

Odense, 5000, Denmark

Location

MeSH Terms

Interventions

Metformin; Codeine

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Study Officials

• Kim Brøsen, professor, chief physcian

  University of Southern Denmark

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Model Details: 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.

Study Record Dates

• First Submitted: October 25, 2017
• First Posted: November 7, 2017
• Study Start: March 1, 2018
• Primary Completion: June 13, 2020
• Study Completion: June 13, 2020
• Last Updated: June 25, 2020

Record last verified: 2018-01

Locations

DK (1)