Clinical trial NCT03335423: Inter- and Intra-individual Variations in Metformin Pharmacokinetics - The Importance of Genes and Drug Interactions
Official title: Inter- and Intra-individual Variations in Metformin Pharmacokinetics - The Importance of Genes and Drug Interactions
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Metformin
Organic Cation Transporter 1
Codeine
Lead sponsor: University of Southern Denmark
Sponsor class: OTHER
First posted: 2017-11-07
Enrollment: 228
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: BASIC_SCIENCE

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

Eligibility 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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Primary outcomes:
measure: Metformin AUC
timeFrame: 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.
measure: Metformin AUC
timeFrame: 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:
measure: Codeine AUC
timeFrame: 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
measure: Lactate AUC
timeFrame: Blood samples for lactate will be drawn in each arm after metformin ingestion for 24 hours at suitable times
Other outcomes:
Locations:
city: Odense
country: Denmark
facility: The department of clinical pharmacy and pharmacology
Study officials:
affiliation: University of Southern Denmark
name: Kim Brøsen, professor, chief physcian
role: STUDY_CHAIR
References: