Mechanistic modelling of tesaglitazar pharmacokinetic data in subjects with various degrees of renal function: evidence of interconversion
2008 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 65, no 6, 855-863 p.Article in journal (Refereed) Published
To develop a mechanistic pharmacokinetic (PK) model for tesaglitazar and its metabolite (an acyl glucuronide) following oral administration of tesaglitazar to subjects with varying renal function, and derive an explanation for the increased plasma exposure of tesaglitazar in subjects with impaired renal function.
Data were from a 6-week study in subjects with renal insufficiency and matched controls undergoing repeated oral dosing with tesaglitazar (n = 41). Compartmental population PK modelling was employed to describe the PK of tesaglitazar and its metabolite, in plasma and urine, simultaneously. Two hypotheses were tested to investigate the increased exposure of tesaglitazar in subjects with renal functional impairment: tesaglitazar metabolism is correlated with renal function, or metabolite elimination is reduced in renal insufficiency, leading to increased hydrolysis (interconversion) to the parent compound via biliary circulation.
The hypothesis for interconversion was best supported by the data. The population PK model included first-order absorption, two-compartment disposition and separate renal (0.027 l h(-1)) and metabolic (1.9 l h(-1)) clearances for tesaglitazar. The model for the metabolite; one-compartment disposition with renal (saturable, V-max = 0.19 mu mol l(-1) and Km = 0.04 mmol l(-1)) and nonrenal clearances (1.2 l h(-1)), biliary secretion (12 h(-1)) to the gut, where interconversion and reabsorption (0.8 h(-1)) of tesaglitazar occurred.
A mechanistic population PK model for tesaglitazar and its metabolite was developed in subjects with varying degrees of renal insufficiency. The model and data give insight into the likely mechanism (interconversion) of the increased tesaglitazar exposure in renally impaired subjects, and separate elimination and interconversion processes without dosing of the metabolite.
Place, publisher, year, edition, pages
2008. Vol. 65, no 6, 855-863 p.
acyl glucuronide, interconversion, mechanistic modelling, NONMEM, population pharmacokinetics, tesaglitazar
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-97051DOI: 10.1111/j.1365-2125.2008.03110.xISI: 000255751300008OAI: oai:DiVA.org:uu-97051DiVA: diva2:171832