Predicting individual responses to pravastatin using a physiologically based kinetic model for plasma cholesterol levels
Pas, N.C.A. van de; Rullmann, J. ; Woutersen, R.A. ; Ommen, B. van; Rietjens, I. ; Graaf, A.A. de - \ 2014
Journal of Pharmacokinetics and Pharmacodynamics 41 (2014)4. - ISSN 1567-567X - p. 351 - 362.
coa reductase inhibitors - statin therapy - lowering-therapy - ldl cholesterol - hepg2 cells - atorvastatin - simvastatin - absorption - metabolism - trial
We used a previously developed physiologically based kinetic (PBK) model to analyze the effect of individual variations in metabolism and transport of cholesterol on pravastatin response. The PBK model is based on kinetic expressions for 21 reactions that interconnect eight different body cholesterol pools including plasma HDL and non-HDL cholesterol. A pravastatin pharmacokinetic model was constructed and the simulated hepatic pravastatin concentration was used to modulate the reaction rate constant of hepatic free cholesterol synthesis in the PBK model. The integrated model was then used to predict plasma cholesterol concentrations as a function of pravastatin dose. Predicted versus observed values at 40 mg/d pravastatin were 15 versus 22 % reduction of total plasma cholesterol, and 10 versus 5.6 % increase of HDL cholesterol. A population of 7,609 virtual subjects was generated using a Monte Carlo approach, and the response to a 40 mg/d pravastatin dose was simulated for each subject. Linear regression analysis of the pravastatin response in this virtual population showed that hepatic and peripheral cholesterol synthesis had the largest regression coefficients for the non-HDL-C response. However, the modeling also showed that these processes alone did not suffice to predict non-HDL-C response to pravastatin, contradicting the hypothesis that people with high cholesterol synthesis rates are good statin responders. In conclusion, we have developed a PBK model that is able to accurately describe the effect of pravastatin treatment on plasma cholesterol concentrations and can be used to provide insight in the mechanisms behind individual variation in statin response.
Plasma proprotein convertase subtilisin kexin type 9 is not altered in subjects with impaired glucose metabolism and type 2 diabetes mellitus, but its relationship with non-HDL cholesterol and apolipoprotein B may be modified by type 2 diabetes mellitus: the CODAM study
Brouwers, M.C.G.J. ; Troutt, J.S. ; Greevenbroek, M.M.J. van; Ferreira, I. ; Feskens, E.J.M. ; Kallen, C.J.H. van der; Schaper, N.C. ; Schalkwijk, C.G. ; Konrad, R.J. ; C.D.A., Stehouwer - \ 2011
Atherosclerosis 217 (2011)1. - ISSN 0021-9150 - p. 263 - 267.
density-lipoprotein cholesterol - ldl cholesterol - pcsk9 - insulin - atorvastatin - fenofibrate - disease
OBJECTIVE: Type 2 diabetes mellitus (T2DM) is associated with elevated plasma apolipoprotein B and triglycerides levels, reduced HDL cholesterol and the presence of small-dense LDL particles. The present study was conducted to investigate the role of plasma proprotein convertase subtilisin kexin type 9 (PCSK9) levels, a regulator of LDL-receptor expression, in the occurrence of diabetic dyslipidemia. METHODS: Plasma PCSK9 was measured in a cohort of subjects with normal glucose metabolism (NGM; n=288), impaired glucose metabolism (IGM; n=121) and type 2 diabetes mellitus (T2DM; n=139) to study whether its relation with plasma apolipoprotein B, triglycerides, total cholesterol, non-HDL cholesterol, LDL cholesterol and HDL cholesterol differed by levels of glucose metabolism status. RESULTS: Plasma PCSK9 levels were not different between the three groups (82, 82 and 80 ng/mL in NGM, IGM and T2DM, respectively). PCSK9 was positively associated with total cholesterol, non-HDL cholesterol, LDL cholesterol, apolipoprotein B and triglycerides levels in all subgroups. The regression slopes for the associations with non-HDL cholesterol were steeper among individuals with T2DM than with NGM (ß = 0.016 versus ß=0.009, p-interaction=0.05). Similar results were obtained for the relation with apolipoprotein B (ß = 0.004 versus ß = 0.002, p-interaction=0.09). CONCLUSIONS: Although glucose metabolism status per se is not associated with plasma PCSK9 levels, the presence of T2DM may modify the relation between plasma PCSK9 and non-HDL cholesterol and apolipoprotein B. These observations should be regarded as hypothesis generating for further studies aimed at elucidating the role of PCSK9 in the pathogenesis and treatment of diabetic dyslipidemia.