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

Gadkar K, Budha N, Baruch A, Davis JD, Fielder P, Ramanujan S - CPT Pharmacometrics Syst Pharmacol (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

No MeSH data available.


Related in: MedlinePlus

Phase I virtual population selection and validation: LDLc, PCSK9, and LDLR for the virtual population at baseline and post high dose atorvastatin treatment. LDLc, low density lipoprotein cholesterol; LDLR, low density lipoprotein receptors.
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fig1: Phase I virtual population selection and validation: LDLc, PCSK9, and LDLR for the virtual population at baseline and post high dose atorvastatin treatment. LDLc, low density lipoprotein cholesterol; LDLR, low density lipoprotein receptors.

Mentions: Statin response calibration and validation. Sustained inhibition of cholesterol synthesis by high dose (40–80 mg) atorvastatin was calibrated at 80% (CV = 25%) to capture a ~50% reduction in LDLc reported in the clinical literature.16Figure 1 shows the corresponding LDLc distribution at baseline and after atorvastatin treatment for the phase I virtual population. In order to partially validate the statin implementation and test its ability to capture known effects of the drug on the modeled behaviors, we verified that simulations in the phase I population recapitulated the increase in PCSK9 reported clinically for statin treatment.17Figure 1 confirms a simulated mean increase of 35% in PCSK9 levels as a result of high dose atorvastatin treatment, consistent with the reported range of 20–50%,17 offering validation that the regulation of PCSK9 synthesis and LDLR expression modeled based on preclinical data18,19,20 appropriately reproduces clinical behavior.


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

Gadkar K, Budha N, Baruch A, Davis JD, Fielder P, Ramanujan S - CPT Pharmacometrics Syst Pharmacol (2014)

Phase I virtual population selection and validation: LDLc, PCSK9, and LDLR for the virtual population at baseline and post high dose atorvastatin treatment. LDLc, low density lipoprotein cholesterol; LDLR, low density lipoprotein receptors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4260002&req=5

fig1: Phase I virtual population selection and validation: LDLc, PCSK9, and LDLR for the virtual population at baseline and post high dose atorvastatin treatment. LDLc, low density lipoprotein cholesterol; LDLR, low density lipoprotein receptors.
Mentions: Statin response calibration and validation. Sustained inhibition of cholesterol synthesis by high dose (40–80 mg) atorvastatin was calibrated at 80% (CV = 25%) to capture a ~50% reduction in LDLc reported in the clinical literature.16Figure 1 shows the corresponding LDLc distribution at baseline and after atorvastatin treatment for the phase I virtual population. In order to partially validate the statin implementation and test its ability to capture known effects of the drug on the modeled behaviors, we verified that simulations in the phase I population recapitulated the increase in PCSK9 reported clinically for statin treatment.17Figure 1 confirms a simulated mean increase of 35% in PCSK9 levels as a result of high dose atorvastatin treatment, consistent with the reported range of 20–50%,17 offering validation that the regulation of PCSK9 synthesis and LDLR expression modeled based on preclinical data18,19,20 appropriately reproduces clinical behavior.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

No MeSH data available.


Related in: MedlinePlus