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Review
. 2019 May 23;14:3819-3830.
doi: 10.2147/IJN.S139450. eCollection 2019.

CPX-351: A Nanoscale Liposomal Co-Formulation of Daunorubicin and Cytarabine With Unique Biodistribution and Tumor Cell Uptake Properties

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Free PMC article
Review

CPX-351: A Nanoscale Liposomal Co-Formulation of Daunorubicin and Cytarabine With Unique Biodistribution and Tumor Cell Uptake Properties

Lawrence D Mayer et al. Int J Nanomedicine. .
Free PMC article

Abstract

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: CPX-351; acute myeloid leukemia; cytarabine; daunorubicin; molar ratio; nanoscale liposomes.

Conflict of interest statement

AC Louie, P Tardi, and LD Mayer are employees of Jazz Pharmaceuticals, Inc. LD Mayer reports personal fees from Jazz Pharmaceuticals, outside the submitted work; in addition, LD Mayer has patents issued for CombiPlex drug combinations, low cholesterol liposomes, clinical use of CPX-351, copper-mediated drug encapsulation, and synergistic ratio of cytarabine and daunorubicin. P Tardi reports personal fees from Celator and Jazz Pharmaceuticals during the conduct of the study; personal fees from Celator and Jazz Pharmaceuticals outside the submitted work; and several patents issued to Celator Pharmaceuticals (patent nos: 7238367, 8518437, 8022279, 7850990, and 10028912). AC Louie has a patent for CPX-351. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Overall survival in the Phase III clinical study comparing CPX-351 and cytarabine:daunorubicin 7+3 in patients with newly diagnosed high-risk/sAML. Notes: Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (Cytarabine: daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36(26):2684–2692. Reprinted with permission. ©(2018) American Society of Clinical Oncology. All rights reserved. Abbreviations: CI, confidence interval; sAML, secondary acute myeloid leukemia.
Figure 2
Figure 2
Schematic representation of the CPX-351 liposome (A). CPX-351 contains bilayers of DSPC, DSPG, and cholesterol at a 7:2:1 molar ratio. This structure 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. Cryogenic transmission electron microscopy images of CPX-351 (B). The formulation shows a regular spherical morphology that is primarily bilamellar. The scale bar represents 100 nm. Notes: Image (A) Copyright©(2018). Future Medicine Ltd. Reproduced from Tolcher AW, Mayer LD. Improving combination cancer therapy: the CombiPlex development platform. Future Oncol. 2018;14(13):1317–1332. Abbreviations: DSPC, distearoylphosphatidylcholine; DSPG, distearoylphosphatidylglycerol.
Figure 3
Figure 3
Molar ratio of cytarabine to daunorubicin following infusion of CPX-351 at a dose of cytarabine 101 mg/m2 plus daunorubicin 44 mg/m2 over 90 mins. Following infusion administered on day 1: dashed line; following infusion administered on Day 5: solid line (n=13). Error bars represent standard deviation. Notes: Reprinted from Leuk Res, 36(10), Feldman EJ, Kolitz JE, Trang JM, et al, Pharmacokinetics of CPX-351; a nano-scale liposomal fixed molar ratio formulation of cytarabine: daunorubicin, in patients with advanced leukemia, 1283–1289, Copyright (2012), with permission from Elsevier.

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