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- Title
Use of an indirect effect model to describe the LDL cholesterol-lowering effect by statins in hypercholesterolaemic patients.
- Authors
Faltaos, Demiana William; Urien, Saïk; Carreau, Valérie; Chauvenet, Marina; Hulot, Jean Sebastian; Giral, Philippe; Bruckert, Eric; Lechat, Philippe
- Abstract
Statins are the most commonly prescribed agents for the treatment of hypercholesterolaemia. This is due to their efficacy in reducing low-density lipoprotein cholesterol (LDL) level which is the primary goal of the treatment especially for patients with multiple risk factors or with established coronary heart diseases. The purpose of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes the LDL-lowering process in patients with hypercholesterolaemia treated with atorvastatin, fluvastatin or simvastatin. A total of 100 patients were studied retrospectively. They received atorvastatin ( n = 57), fluvastatin ( n = 26) or simvastatin ( n = 17). As no pharmacokinetic data were available, the absorption rate was fixed to 1/h and atorvastatin, simvastatin and fluvastatin elimination half-lives were fixed to 14, 2 and 2.5 h respectively. A total of 309 LDL levels were measured and the data were analysed bynonmem v. The time course of the LDL-lowering effect of statins was described by an indirect-response model with precursor (LDL synthesis, input rate Kin) and response (circulating LDL, input and output rates K) compartments. The following parameters were estimated: LDL input rate ( Kin) 0.14 ± 0.015 g/L/day (mean ± SD); inhibition fraction of Kin (INH) 0.21 ± 0.017; and dose producing 50% increase of LDL removal (D50), 26 ± 7.8, 1.3 ± 0.48 and 15 ± 5.25 mg for atorvastatin, simvastatin and fluvastatin, respectively. Gender, bodyweight, age, calories/day, sugar/day, lipids/day, hyperlipidaemia types and waist/hip circumference, renal and hepatic functions had no effect on the pharmacodynamic parameters. The pharmacodynamic parameters for the three statins were accurately estimated. The PK/PD model developed successfully predicted the time course of the LDL-lowering effect of statins.
- Subjects
STATINS (Cardiovascular agents); LOW density lipoproteins; HYPERCHOLESTEREMIA; CORONARY disease; PHARMACOKINETICS
- Publication
Fundamental & Clinical Pharmacology, 2006, Vol 20, Issue 3, p321
- ISSN
0767-3981
- Publication type
Article
- DOI
10.1111/j.1472-8206.2006.00404.x