Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia

Abstract Evinacumab, an angiopoietin‐like protein 3 (ANGPTL3) inhibitor, has been shown to significantly reduce low‐density lipoprotein cholesterol (LDL‐C) in patients with homozygous familial hypercholesterolemia (HoFH). This work characterized the population pharmacokinetics (PK)/pharmacodynamics...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Xia Pu, Mark Sale, Feng Yang, Yi Zhang, 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/7d13c590a1c64df5a16b0dbf274cfafe
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:7d13c590a1c64df5a16b0dbf274cfafe
record_format	dspace
spelling	oai:doaj.org-article:7d13c590a1c64df5a16b0dbf274cfafe2021-11-15T18:41:54ZPopulation pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia2163-830610.1002/psp4.12711https://doaj.org/article/7d13c590a1c64df5a16b0dbf274cfafe2021-11-01T00:00:00Zhttps://doi.org/10.1002/psp4.12711https://doaj.org/toc/2163-8306Abstract Evinacumab, an angiopoietin‐like protein 3 (ANGPTL3) inhibitor, has been shown to significantly reduce low‐density lipoprotein cholesterol (LDL‐C) in patients with homozygous familial hypercholesterolemia (HoFH). This work characterized the population pharmacokinetics (PK)/pharmacodynamics (PD) of evinacumab using pooled phase III clinical data. Total evinacumab PK were described by a two‐compartment model with combined linear and saturable (Michaelis–Menten) elimination, and first‐order absorption. At clinically relevant concentrations, plasma drug concentrations were mainly influenced by the linear clearance pathway. Although the maximum target‐mediated rate of elimination (Vmax) parameter for the saturable pathway was found to be positively related to baseline ANGPLTL3, variability in body weight contributed more to the variability in evinacumab exposure than variability in ANGPTL3. An effect of HoFH versus healthy volunteers on Vmax was also identified. Weight‐based dosing regimens resulted in consistent evinacumab exposure across weight ranges. An indirect exposure–response model adequately described the relationship between evinacumab and LDL‐C, where drug concentration is assumed to inhibit LDL‐C production. The final population PK/PD model included two nonclinically significant covariates (race and baseline body weight) on the maximum drug‐induced inhibitory effect (Imax) and one (baseline LDL‐C) on the evinacumab concentration inducing 50% of Imax (IC50). A smaller IC50 was observed in patients with higher baseline LDL‐C, suggesting greater sensitivity to treatment. Population exposure–response analysis permitted estimation of derived PD parameters and individual LDL‐C levels over time for patients with HoFH. The model accurately predicted the proportion of patients with HoFH achieving prespecified LDL‐C goals with evinacumab during the ELIPSE HoFH study, further supporting a dosing strategy.Xia PuMark SaleFeng YangYi ZhangJohn D. DavisNidal Al‐HunitiWileyarticleTherapeutics. PharmacologyRM1-950ENCPT: Pharmacometrics & Systems Pharmacology, Vol 10, Iss 11, Pp 1412-1421 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950
spellingShingle	Therapeutics. Pharmacology RM1-950 Xia Pu Mark Sale Feng Yang Yi Zhang John D. Davis Nidal Al‐Huniti Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia
description	Abstract Evinacumab, an angiopoietin‐like protein 3 (ANGPTL3) inhibitor, has been shown to significantly reduce low‐density lipoprotein cholesterol (LDL‐C) in patients with homozygous familial hypercholesterolemia (HoFH). This work characterized the population pharmacokinetics (PK)/pharmacodynamics (PD) of evinacumab using pooled phase III clinical data. Total evinacumab PK were described by a two‐compartment model with combined linear and saturable (Michaelis–Menten) elimination, and first‐order absorption. At clinically relevant concentrations, plasma drug concentrations were mainly influenced by the linear clearance pathway. Although the maximum target‐mediated rate of elimination (Vmax) parameter for the saturable pathway was found to be positively related to baseline ANGPLTL3, variability in body weight contributed more to the variability in evinacumab exposure than variability in ANGPTL3. An effect of HoFH versus healthy volunteers on Vmax was also identified. Weight‐based dosing regimens resulted in consistent evinacumab exposure across weight ranges. An indirect exposure–response model adequately described the relationship between evinacumab and LDL‐C, where drug concentration is assumed to inhibit LDL‐C production. The final population PK/PD model included two nonclinically significant covariates (race and baseline body weight) on the maximum drug‐induced inhibitory effect (Imax) and one (baseline LDL‐C) on the evinacumab concentration inducing 50% of Imax (IC50). A smaller IC50 was observed in patients with higher baseline LDL‐C, suggesting greater sensitivity to treatment. Population exposure–response analysis permitted estimation of derived PD parameters and individual LDL‐C levels over time for patients with HoFH. The model accurately predicted the proportion of patients with HoFH achieving prespecified LDL‐C goals with evinacumab during the ELIPSE HoFH study, further supporting a dosing strategy.
format	article
author	Xia Pu Mark Sale Feng Yang Yi Zhang John D. Davis Nidal Al‐Huniti
author_facet	Xia Pu Mark Sale Feng Yang Yi Zhang John D. Davis Nidal Al‐Huniti
author_sort	Xia Pu
title	Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia
title_short	Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia
title_full	Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia
title_fullStr	Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia
title_full_unstemmed	Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia
title_sort	population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/7d13c590a1c64df5a16b0dbf274cfafe
work_keys_str_mv	AT xiapu populationpharmacokineticsandexposureresponsemodelingforevinacumabinhomozygousfamilialhypercholesterolemia AT marksale populationpharmacokineticsandexposureresponsemodelingforevinacumabinhomozygousfamilialhypercholesterolemia AT fengyang populationpharmacokineticsandexposureresponsemodelingforevinacumabinhomozygousfamilialhypercholesterolemia AT yizhang populationpharmacokineticsandexposureresponsemodelingforevinacumabinhomozygousfamilialhypercholesterolemia AT johnddavis populationpharmacokineticsandexposureresponsemodelingforevinacumabinhomozygousfamilialhypercholesterolemia AT nidalalhuniti populationpharmacokineticsandexposureresponsemodelingforevinacumabinhomozygousfamilialhypercholesterolemia
_version_	1718426851860283392

Population pharmacokinetics and exposure–response modeling for evinacumab in homozygous familial hypercholesterolemia

Ejemplares similares