Characterization of changes in HbA1c in patients with and without secondary failure after metformin treatments by a population pharmacodynamic analysis using mixture models

Yoko Tamaki, Kunio Maema, Makoto Kakara, Masato Fukae, Ryoko Kinoshita, Yushi Kashihara, Shota Muraki, Takeshi Hirota, Ichiro Ieiri

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The objective of the present study was to develop a population pharmacodynamic (PPD) model to describe the glycated hemoglobin (HbA1c)-lowering effects of metformin in type 2 diabetes mellitus patients with and without secondary failure and to characterize changes in HbA1c levels in the two subpopulations using a mixture model. Information on patients was collected retrospectively from electronic medical records. In this study, the mixture model was used to characterize the bimodal effects of metformin. A PPD analysis was performed using NONMEM 7.3.0. A physiological indirect response model, based on 829 HbA1c levels of 69 patients, described the time course for the HbA1c-lowering effects of metformin. Evidence for the different effectiveness of metformin subpopulations was provided using the mixture model. In the final PPD model, the inhibition effect was constant over a study duration in a patient subpopulation without secondary failure. In contrast, the inhibition effect decreased as a function of time after start of metformin treatment in a subpopulation with secondary failure. These results indicated that HbA1c improvements appeared to deteriorate over time in patients with secondary failure. In a PPD analysis of metformin, it was possible to assign patients with secondary failure using the mixture model.

Original languageEnglish
Pages (from-to)264-269
Number of pages6
JournalDrug metabolism and pharmacokinetics
Volume33
Issue number6
DOIs
Publication statusPublished - Dec 1 2018

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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