Demiana William Faltaos(1), Saïk Urien(1), Valérie Carreau(2), Marina Chauvenet(2), Jean Sebastian Hulot(1), Philippe Giral(2), Eric Bruckert(2), Philippe Lechat(1).
(1) Pharmacology Department of Pitié-salpétriêre University Hospital, Paris, France, (2) Endocrinology and Metabolism department of Pitié-salpétriêre University Hospital, Paris, France
Introduction: Statins (HMG-COA redustase inhibitors) are the most commonly prescribed agents for the treatment of hypercholesterolemia. This is due to their efficacy in reducing LDL cholesterol (LDL) level which is the primary goal of the treatment especially for patients with multiple risk factors or with established coronary heart diseases.Â
Aim: To develop a K/PD model that describes the LDL lowering process in patients with hypercholesterolemia treated with atorvastatin, fluvastatin, simvastatin.
Methods: 100 patients were studied retrospectively: 57 treated with atorvastatin, 26 with fluvastatin and 17 with simvastatin. The Lipid panels were obtained for each patient at the treatment initiation and then 1 to 9 other compliance panels were obtained at different time intervals. 309LDL levels were measured and the data was analysed by NONMEM V.
Results: The time course of the LDL lowering effect of statins was ascribed to an indirect response model with precursor compartment in which the first compartment corresponds to a pool of LDL synthesis (rate Kin ) and the second one corresponds to the circulating LDL pool (site of measurement of the response).The time pattern of the response variable can be affected by statins which can alter either the production rate (Kin ) or the elimination process ( K).
The differential equations connected to the model were
dP/dt = Kin.(1-INH) – K.PÂ Â Â Â Â Â Â (1)
the LDL variation in the precursor compartment, and
dR/dt = K P – (STIM).K.RÂ Â Â Â Â Â Â (2)
the circulating LDL compartment
where the P and R denote the precursor and response compartments, INH and SIM denote the drug inhibition and stimulation effects respectively. Stimulation (STIM) was related to the drug amount (D) in the body as follows
STIM = 1+D/( D + D50)
where, D50 denotes the dose that produced a 50 % stimulation of the LDL elimination. Since no pharmacokinetic data was available in this study, the absorption rate was fixed to 24 day -1 and atorvastatin, fluvastatin and simvastatin elimination half-lives were fixed to 0.9, 0.7, 1.75 day respectively. Gender, bodyweight, age, calories/day, sugar/day, lipids/day, hyperlipidemia types and waist /hip circumference did not have any effect on the pharmacodynamic parameters.
Conclusions: The pharmacodynamic parameters for the three statins were accurately estimated. The K/PD model developed successfully predicted the time course of LDL.
Reference: PAGE 14 (2005) Abstr 760 [www.page-meeting.org/?abstract=760]
Poster: poster