Models for plasma glucose, HbA1c, and hemoglobin interrelationships in patients with type 2 diabetes following tesaglitazar treatment.
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.
Hamrén
B
B
Department of Medical Science, Clinical Pharmacology, AstraZeneca R&D Mölndal, Mölndal, Sweden. bengt.hamren@astrazeneca.com
Björk
E
E
Sunzel
M
M
Karlsson
Mo
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000476:Alkanesulfonates / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D005215:Fasting; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006438:Hemodilution; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D047493:PPAR alpha / Q000819:agonists; D047495:PPAR gamma / Q000819:agonists; D010666:Phenylpropionates / Q000627:therapeutic use*
D000476:Alkanesulfonates; D015415:Biomarkers; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D006454:Hemoglobins; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; C517652:hemoglobin A1c protein, human; C501413:tesaglitazar