CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties

Lawrence D Mayer, Paul Tardi, Arthur C LouieJazz Pharmaceuticals, Inc., Palo Alto, CA, USAAbstract: Combination regimens are a standard of care for many cancers. However, components of such regimens are typically first developed individually and subsequently combined using strategies to minimize tox...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Mayer LD, Tardi P, Louie AC
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	acute myeloid leukemia CPX-351 cytarabine daunorubicin molar ratio nanoscale liposomes Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/6cfd77ea067b482db2d4c973b6435aac
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:6cfd77ea067b482db2d4c973b6435aac
record_format	dspace
spelling	oai:doaj.org-article:6cfd77ea067b482db2d4c973b6435aac2021-12-02T03:16:18ZCPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties1178-2013https://doaj.org/article/6cfd77ea067b482db2d4c973b6435aac2019-05-01T00:00:00Zhttps://www.dovepress.com/cpx-351-a-nanoscale-liposomal-co-formulation-of-daunorubicin-and-cytar-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Lawrence D Mayer, Paul Tardi, Arthur C LouieJazz Pharmaceuticals, Inc., Palo Alto, CA, USAAbstract: Combination regimens are a standard of care for many cancers. However, components of such regimens are typically first developed individually and subsequently combined using strategies to minimize toxicity. Little or no consideration is given to strategies that potentially maximize efficacy. In contrast, CPX-351 (Vyxeos®) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that was rationally designed to improve efficacy over the traditional 7+3 cytarabine/daunorubicin chemotherapy regimen for patients with acute myeloid leukemia (AML). The notable clinical efficacy of CPX-351 is achieved through maintenance of a synergistic 5:1 molar ratio of cytarabine and daunorubicin within the liposome after intravenous injection. The CPX-351 liposome, which is formulated to contain bilayers of distearoylphosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol at a 7:2:1 molar ratio and remains in a gel phase at body temperature, provides stability without polyethylene glycol, controlled release of cytarabine and daunorubicin, limited systemic drug distribution, and preferential internalization within malignant myeloblasts in the bone marrow via active uptake of liposomes into cytoplasmic vacuoles. Thus, the CPX-351 liposome protects cytarabine and daunorubicin from metabolism and elimination, while overcoming pharmacokinetic differences between the two agents. In clinical studies, these liposome properties markedly increased the elimination half-life of CPX-351 versus free cytarabine and daunorubicin and maintained a synergistic drug ratio for over 24 hrs after administration. Preferential uptake of liposomes by leukemia cells suggests that relatively large amounts of cytarabine and daunorubicin enter malignant cells via liposomes, potentially bypassing P-glycoprotein-based efflux pumps, which are important mediators of chemotherapy resistance, and contribute to the rapid clearance of leukemia cells from the circulation and bone marrow. These pharmacologic advantages, a direct consequence of properties of the encapsulating liposome, may explain the efficacy of CPX-351 in patients with newly diagnosed high-risk/secondary AML and the reduced drug exposure in off-target tissues that contribute to a manageable safety profile.Keywords: acute myeloid leukemia, CPX-351, cytarabine, daunorubicin, molar ratio, nanoscale liposomesMayer LDTardi PLouie ACDove Medical Pressarticleacute myeloid leukemiaCPX-351cytarabinedaunorubicinmolar rationanoscale liposomesMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 3819-3830 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	acute myeloid leukemia CPX-351 cytarabine daunorubicin molar ratio nanoscale liposomes Medicine (General) R5-920
spellingShingle	acute myeloid leukemia CPX-351 cytarabine daunorubicin molar ratio nanoscale liposomes Medicine (General) R5-920 Mayer LD Tardi P Louie AC CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties
description	Lawrence D Mayer, Paul Tardi, Arthur C LouieJazz Pharmaceuticals, Inc., Palo Alto, CA, USAAbstract: Combination regimens are a standard of care for many cancers. However, components of such regimens are typically first developed individually and subsequently combined using strategies to minimize toxicity. Little or no consideration is given to strategies that potentially maximize efficacy. In contrast, CPX-351 (Vyxeos®) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that was rationally designed to improve efficacy over the traditional 7+3 cytarabine/daunorubicin chemotherapy regimen for patients with acute myeloid leukemia (AML). The notable clinical efficacy of CPX-351 is achieved through maintenance of a synergistic 5:1 molar ratio of cytarabine and daunorubicin within the liposome after intravenous injection. The CPX-351 liposome, which is formulated to contain bilayers of distearoylphosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol at a 7:2:1 molar ratio and remains in a gel phase at body temperature, provides stability without polyethylene glycol, controlled release of cytarabine and daunorubicin, limited systemic drug distribution, and preferential internalization within malignant myeloblasts in the bone marrow via active uptake of liposomes into cytoplasmic vacuoles. Thus, the CPX-351 liposome protects cytarabine and daunorubicin from metabolism and elimination, while overcoming pharmacokinetic differences between the two agents. In clinical studies, these liposome properties markedly increased the elimination half-life of CPX-351 versus free cytarabine and daunorubicin and maintained a synergistic drug ratio for over 24 hrs after administration. Preferential uptake of liposomes by leukemia cells suggests that relatively large amounts of cytarabine and daunorubicin enter malignant cells via liposomes, potentially bypassing P-glycoprotein-based efflux pumps, which are important mediators of chemotherapy resistance, and contribute to the rapid clearance of leukemia cells from the circulation and bone marrow. These pharmacologic advantages, a direct consequence of properties of the encapsulating liposome, may explain the efficacy of CPX-351 in patients with newly diagnosed high-risk/secondary AML and the reduced drug exposure in off-target tissues that contribute to a manageable safety profile.Keywords: acute myeloid leukemia, CPX-351, cytarabine, daunorubicin, molar ratio, nanoscale liposomes
format	article
author	Mayer LD Tardi P Louie AC
author_facet	Mayer LD Tardi P Louie AC
author_sort	Mayer LD
title	CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties
title_short	CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties
title_full	CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties
title_fullStr	CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties
title_full_unstemmed	CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties
title_sort	cpx-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/6cfd77ea067b482db2d4c973b6435aac
work_keys_str_mv	AT mayerld cpx351ananoscaleliposomalcoformulationofdaunorubicinandcytarabinewithuniquebiodistributionandtumorcelluptakeproperties AT tardip cpx351ananoscaleliposomalcoformulationofdaunorubicinandcytarabinewithuniquebiodistributionandtumorcelluptakeproperties AT louieac cpx351ananoscaleliposomalcoformulationofdaunorubicinandcytarabinewithuniquebiodistributionandtumorcelluptakeproperties
_version_	1718401859868164096

CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties

Ejemplares similares