Models for plasma glucose, HbA1c, and hemoglobin interrelationships in patients with type 2 diabetes following tesaglitazar treatment

Clin Pharmacol Ther. 2008 Aug;84(2):228-35. doi: 10.1038/clpt.2008.2. Epub 2008 Mar 19.

Abstract

Pharmacokinetic (PK) pharmacodynamic (PD) modeling was applied to understand and quantitate the interplay between tesaglitazar (a peroxisome proliferator-activated receptor alpha/gamma agonist) exposure, fasting plasma glucose (FPG), hemoglobin (Hb), and glycosylated hemoglobin (HbA1c) in type 2 diabetic patients. Data originated from a 12-week dose-ranging study with tesaglitazar. The primary objective was to develop a mechanism-based PD model for the FPG-HbA1c relationship. The secondary objective was to investigate possible mechanisms for the tesaglitazar effect on Hb. Following initiation of tesaglitazar therapy, time to new FPG steady state was approximately 9 weeks, and tesaglitazar potency in females was twice that in males. The model included aging of red blood cells (RBCs) using a transit compartment approach. The RBC life span was estimated to 135 days. The transformation from RBC to HbA1c was modeled as an FPG-dependent process. The model indicated that the tesaglitazar effect on Hb was caused by hemodilution of RBCs.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alkanesulfonates / therapeutic use*
  • Biomarkers / blood
  • Blood Glucose / metabolism*
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Fasting
  • Female
  • Glycated Hemoglobin A / metabolism*
  • Hemodilution
  • Hemoglobins / metabolism*
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Male
  • Middle Aged
  • PPAR alpha / agonists
  • PPAR gamma / agonists
  • Phenylpropionates / therapeutic use*

Substances

  • Alkanesulfonates
  • Biomarkers
  • Blood Glucose
  • Glycated Hemoglobin A
  • Hemoglobins
  • Hypoglycemic Agents
  • PPAR alpha
  • PPAR gamma
  • Phenylpropionates
  • hemoglobin A1c protein, human
  • tesaglitazar