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Pharmacokinetic‐Pharmacodynamic Assessment of the Interrelationships Between Tesaglitazar Exposure and Renal Function in Patients With Type 2 Diabetes Mellitus
Author(s) -
Hamrén Bengt,
Öhman K. Peter,
Svensson Maria K.,
Karlsson Mats O.
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270011416937
Subject(s) - renal function , medicine , pharmacodynamics , diabetes mellitus , urology , pharmacokinetics , population , endocrinology , filtration fraction , kidney disease , pharmacology , renal blood flow , environmental health
The effects of tesaglitazar on renal function (assessed as urinary clearance of 125 I‐sodium iothalamate or estimated by the modification of diet in renal disease formula) were studied in a 24‐week open‐label trial in type 2 diabetes mellitus patients randomized to daily doses of either tesaglitazar 2 mg or pioglitazone 45 mg. The aim of the analysis was to develop a population pharmacokinetic‐pharmacodynamic model that could simultaneously describe the interrelationship between tesaglitazar exposure and reduction in renal function over time in patients with type 2 diabetes mellitus. The pharmacokinetic‐pharmacodynamic model could adequately describe the interplay between tesaglitazar and glomerular filtration rate. A one‐compartment model in which the apparent clearance was influenced by glomerular filtration rate characterized the pharmacokinetics of tesaglitazar. An indirect‐response model was used for the slow time course of change in glomerular filtration rate, which decreased from 100 to 78 mL/min/1.73m 2 after 12 weeks of treatment. All tesaglitazar‐treated patients had a reduction in glomerular filtration rate, and available demographic variables could not explain differences in response. Patients treated with an angiotensin converting enzyme inhibitor were more sensitive to tesaglitazar and had larger glomerular filtration rate decrease compared to nontreated patients. Approximately 8 weeks after discontinuing treatment, mean glomerular filtration rate had returned towards baseline. The model and data give valuable insights into the dynamic changes in glomerular filtration rate over time.