A Mechanistic Systems Pharmacology Model for Prediction of LDL Cholesterol Lowering by PCSK9 Antagonism in Human Dyslipidemic Populations

K Gadkar; N Budha; A Baruch; J D Davis; P Fielder; S Ramanujan

doi:10.1038/psp.2014.47

A Mechanistic Systems Pharmacology Model for Prediction of LDL Cholesterol Lowering by PCSK9 Antagonism in Human Dyslipidemic Populations

CPT Pharmacometrics Syst Pharmacol. 2014 Nov 26;3(11):e149. doi: 10.1038/psp.2014.47.

Authors

K Gadkar¹, N Budha¹, A Baruch¹, J D Davis¹, P Fielder¹, S Ramanujan¹

Affiliation

¹ Preclinical and Translational PKPD, Genentech, South San Francisco, California, USA.

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.