Using a semi-mechanistic model to identify the main sources of variability of metformin pharmacokinetics

Autor: Gustaf J. Wellhagen, Kim Brøsen, Mette Marie Hougaard Christensen, Benjamin Guiastrennec, Maria C. Kjellsson, Tore Bjerregaard Stage
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Adult
Time Factors
Organic Cation Transport Proteins
Pharmacogenomic Variants
Renal function
Administration
Oral
Biological Availability
Urine
Biological Variation
Population/physiology
Biology
Pharmacology
Toxicology
030226 pharmacology & pharmacy
Models
Biological
Polymorphism
Single Nucleotide
03 medical and health sciences
Young Adult
0302 clinical medicine
Metformin/administration & dosage
Pharmacokinetics
medicine
Hypoglycemic Agents
Humans
Gastrointestinal Transit
Volume of distribution
Clinical Trials as Topic
Biological Variation
Individual
Gastrointestinal Absorption/physiology
Acidosis
Lactic/chemically induced
Gastrointestinal Transit/physiology
General Medicine
Middle Aged
Hypoglycemic Agents/administration & dosage
Metformin
Healthy Volunteers
NONMEM
Biological Variation
Population
Gastrointestinal Absorption
030220 oncology & carcinogenesis
Renal physiology
Acidosis
Lactic
medicine.drug
Organic Cation Transport Proteins/genetics
Zdroj: Stage, T B, Wellhagen, G, Christensen, M M H, Guiastrennec, B, Brøsen, K & Kjellsson, M C 2019, ' Using a semi-mechanistic model to identify the main sources of variability of metformin pharmacokinetics ', Basic & Clinical Pharmacology & Toxicology, vol. 124, no. 1, pp. 105-114 . https://doi.org/10.1111/bcpt.13139
Popis: Metformin pharmacokinetics (PK) is highly variable, and researchers have for years tried to shed light on determinants of inter-individual (IIV) and inter-occasion variability (IOV) of metformin PK. We set out to identify the main sources of PK variability using a semi-mechanistic model. We assessed the influence of subject characteristics, including seven genetic variants. Data from three studies of healthy individuals with PK measurements of plasma and urine after single dose or at steady-state were used in this study. In total, 87 subjects were included (16 crossover subjects). Single nucleotide polymorphisms in ATM, OCT1, OCT2, MATE1 and MATE2-K were investigated as dominant, recessive or additive. A three-compartment model with transit absorption and renal elimination with a proportional error was fitted to the data using NONMEM 7.3. Oral parameters were separated from disposition parameters as dose-dependent absolute bioavailability was determined with support from urine data. Clearance was expressed as net renal secretion and filtration, assuming full fraction unbound and fraction excreted. Mean transit time and peripheral volume of distribution were identified as the main sources of variability according to estimates, with 94% IOV and 95% IIV, respectively. Clearance contributed only with 16% IIV. Glomerular filtration rate and body-weight were the only covariates found to affect metformin net secretion, reducing IIV to 14%. None of the genetic variants were found to affect metformin PK. Based on our analysis, finding covariates explaining absorption of metformin is much more valuable in understanding variability and avoiding toxicity than elimination.
Databáze: OpenAIRE
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