A quantitative systems pharmacology modeling platform for evaluating triglyceride profiles in patients with high triglycerides receiving evinacumab

Abstract A model to quantitatively characterize the effect of evinacumab, an investigational monoclonal antibody against angiopoietin‐like protein 3 (ANGPTL3) on lipid trafficking is needed. A quantitative systems pharmacology (QSP) approach was developed to predict the transient responses of differ...

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Autores principales:	Masood Khaksar Toroghi, Jim Bosley, Lyn M. Powell, Yi Zhang, Feng Yang, Xia Pu, John D. Davis, Nidal Al‐Huniti
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/f2c85718b9bd447bb1c865f81dfe8b6c
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spelling	oai:doaj.org-article:f2c85718b9bd447bb1c865f81dfe8b6c2021-11-15T18:41:53ZA quantitative systems pharmacology modeling platform for evaluating triglyceride profiles in patients with high triglycerides receiving evinacumab2163-830610.1002/psp4.12694https://doaj.org/article/f2c85718b9bd447bb1c865f81dfe8b6c2021-11-01T00:00:00Zhttps://doi.org/10.1002/psp4.12694https://doaj.org/toc/2163-8306Abstract A model to quantitatively characterize the effect of evinacumab, an investigational monoclonal antibody against angiopoietin‐like protein 3 (ANGPTL3) on lipid trafficking is needed. A quantitative systems pharmacology (QSP) approach was developed to predict the transient responses of different triglyceride (TG)‐rich lipoprotein particles in response to evinacumab administration. A previously published hepatic lipid model was modified to address specific queries relevant to the mechanism of evinacumab and its effect on lipid metabolism. Modifications included the addition of intermediate‐density lipoprotein and low‐density lipoprotein compartments to address the modulation of lipoprotein lipase (LPL) activity by evinacumab, ANGPTL3 biosynthesis and clearance, and a target‐mediated drug disposition model. A sensitivity analysis guided the creation of virtual patients (VPs). The drug‐free QSP model was found to agree well with clinical data published with the initial hepatic liver model over simulations ranging from 20 to 365 days in duration. The QSP model, including the interaction between LPL and ANGPTL3, was validated against clinical data for total evinacumab, total ANGPTL3, and TG concentrations as well as inhibition of apolipoprotein CIII. Free ANGPTL3 concentration and LPL activity were also modeled. In total, seven VPs were created; the lipid levels of the VPs were found to match the range of responses observed in evinacumab clinical trial data. The QSP model results agreed with clinical data for various subjects and was shown to characterize known TG physiology and drug effects in a range of patient populations with varying levels of TGs, enabling hypothesis testing of evinacumab effects on lipid metabolism.Masood Khaksar ToroghiJim BosleyLyn M. PowellYi ZhangFeng YangXia PuJohn D. DavisNidal Al‐HunitiWileyarticleTherapeutics. PharmacologyRM1-950ENCPT: Pharmacometrics & Systems Pharmacology, Vol 10, Iss 11, Pp 1332-1342 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950
spellingShingle	Therapeutics. Pharmacology RM1-950 Masood Khaksar Toroghi Jim Bosley Lyn M. Powell Yi Zhang Feng Yang Xia Pu John D. Davis Nidal Al‐Huniti A quantitative systems pharmacology modeling platform for evaluating triglyceride profiles in patients with high triglycerides receiving evinacumab
description	Abstract A model to quantitatively characterize the effect of evinacumab, an investigational monoclonal antibody against angiopoietin‐like protein 3 (ANGPTL3) on lipid trafficking is needed. A quantitative systems pharmacology (QSP) approach was developed to predict the transient responses of different triglyceride (TG)‐rich lipoprotein particles in response to evinacumab administration. A previously published hepatic lipid model was modified to address specific queries relevant to the mechanism of evinacumab and its effect on lipid metabolism. Modifications included the addition of intermediate‐density lipoprotein and low‐density lipoprotein compartments to address the modulation of lipoprotein lipase (LPL) activity by evinacumab, ANGPTL3 biosynthesis and clearance, and a target‐mediated drug disposition model. A sensitivity analysis guided the creation of virtual patients (VPs). The drug‐free QSP model was found to agree well with clinical data published with the initial hepatic liver model over simulations ranging from 20 to 365 days in duration. The QSP model, including the interaction between LPL and ANGPTL3, was validated against clinical data for total evinacumab, total ANGPTL3, and TG concentrations as well as inhibition of apolipoprotein CIII. Free ANGPTL3 concentration and LPL activity were also modeled. In total, seven VPs were created; the lipid levels of the VPs were found to match the range of responses observed in evinacumab clinical trial data. The QSP model results agreed with clinical data for various subjects and was shown to characterize known TG physiology and drug effects in a range of patient populations with varying levels of TGs, enabling hypothesis testing of evinacumab effects on lipid metabolism.
format	article
author	Masood Khaksar Toroghi Jim Bosley Lyn M. Powell Yi Zhang Feng Yang Xia Pu John D. Davis Nidal Al‐Huniti
author_facet	Masood Khaksar Toroghi Jim Bosley Lyn M. Powell Yi Zhang Feng Yang Xia Pu John D. Davis Nidal Al‐Huniti
author_sort	Masood Khaksar Toroghi
title	A quantitative systems pharmacology modeling platform for evaluating triglyceride profiles in patients with high triglycerides receiving evinacumab
title_short	A quantitative systems pharmacology modeling platform for evaluating triglyceride profiles in patients with high triglycerides receiving evinacumab
title_full	A quantitative systems pharmacology modeling platform for evaluating triglyceride profiles in patients with high triglycerides receiving evinacumab
title_fullStr	A quantitative systems pharmacology modeling platform for evaluating triglyceride profiles in patients with high triglycerides receiving evinacumab
title_full_unstemmed	A quantitative systems pharmacology modeling platform for evaluating triglyceride profiles in patients with high triglycerides receiving evinacumab
title_sort	quantitative systems pharmacology modeling platform for evaluating triglyceride profiles in patients with high triglycerides receiving evinacumab
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/f2c85718b9bd447bb1c865f81dfe8b6c
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A quantitative systems pharmacology modeling platform for evaluating triglyceride profiles in patients with high triglycerides receiving evinacumab

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