A Mechanistic Systems Pharmacology Model for Prediction of LDL Cholesterol Lowering by PCSK9 Antagonism in Human Dyslipidemic Populations.
CPT Pharmacometrics Syst Pharmacol
; 3: e149, 2014 Nov 26.
Article
en En
| MEDLINE
| ID: mdl-25426564
ABSTRACT
PCSK9 is a promising target for the treatment of hyperlipidemia and cardiovascular disease. A Quantitative Systems Pharmacology model of the mechanisms of action of statin and anti-PCSK9 therapies was developed to predict low density lipoprotein (LDL) changes in response to anti-PCSK9 mAb for different treatment protocols and patient subpopulations. Mechanistic interactions and cross-regulation of LDL, LDL receptor, and PCSK9 were modeled, and numerous virtual subjects were developed and validated against clinical data. Simulations predict a slightly greater maximum percent reduction in LDL cholesterol (LDLc) when anti-PCSK9 is administered on statin background therapy compared to as a monotherapy. The difference results primarily from higher PCSK9 levels in patients on statin background. However, higher PCSK9 levels are also predicted to increase clearance of anti-PCSK9, resulting in a faster rebound of LDLc. Simulations of subjects with impaired LDL receptor (LDLR) function predict compromised anti-PCSK9 responses in patients such as homozygous familial hypercholesterolemics, whose functional LDLR is below 10% of normal.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Tipo de estudio:
Guideline
/
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Revista:
CPT Pharmacometrics Syst Pharmacol
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos