Mina Nikanjam1, Edmund V Capparelli2, Jeffrey E Lancet3, Arthur Louie4, Gary Schiller5. 1. Division of Host-Microbe Systems and Therapeutics, University of California San Diego, 9500 Gilman Drive MC 0657, La Jolla, San Diego, CA, 92093-0657, USA. mnikanjam@ucsd.edu. 2. Division of Host-Microbe Systems and Therapeutics, University of California San Diego, 9500 Gilman Drive MC 0657, La Jolla, San Diego, CA, 92093-0657, USA. 3. H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. 4. Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals, Ewing, NJ, USA. 5. Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Abstract
PURPOSE: CPX-351 is a novel liposomal formulation of cytarabine and daunorubicin which has recently been FDA approved for treatment of acute myeloid leukemia (AML). The current study investigated the pharmacokinetics (PK) of this liposomal formulation. METHODS: CPX-351 PK data (cytarabine, daunorubicin, and metabolites) from a phase I study of relapsed and refractory AML were used for the analysis. Therapy was given days 1, 3, and 5 of induction (3-134 units/m2). We developed a population PK model to characterize CPX-351 disposition. RESULTS: 39 patients (3589 samples) were evaluated. Liposomal cytarabine and daunorubicin were modeled separately with their respective metabolites. A one-compartment model fit the parent compounds well; the metabolites required two-compartment models. Weight was an independent predictor of liposomal volumes; mild renal and liver dysfunction were not predictors of clearance or volume (maximum creatinine 1.6 mg/dL and total bilirubin 1.8 mg/dL). Liposomal clearances of the two drugs were highly correlated and 1000-fold smaller than published non-encapsulated values supporting prolonged encapsulation in the liposome. CONCLUSIONS: The PK model demonstrates prolonged exposure to cytarabine and daunorubicin without increases in non-hematologic toxicity that indicates retention of the drugs within the liposome. The unique pharmacology of this formulation may allow for simplified regimens and improved outcomes.
PURPOSE:CPX-351 is a novel liposomal formulation of cytarabine and daunorubicin which has recently been FDA approved for treatment of acute myeloid leukemia (AML). The current study investigated the pharmacokinetics (PK) of this liposomal formulation. METHODS:CPX-351 PK data (cytarabine, daunorubicin, and metabolites) from a phase I study of relapsed and refractory AML were used for the analysis. Therapy was given days 1, 3, and 5 of induction (3-134 units/m2). We developed a population PK model to characterize CPX-351 disposition. RESULTS: 39 patients (3589 samples) were evaluated. Liposomal cytarabine and daunorubicin were modeled separately with their respective metabolites. A one-compartment model fit the parent compounds well; the metabolites required two-compartment models. Weight was an independent predictor of liposomal volumes; mild renal and liver dysfunction were not predictors of clearance or volume (maximum creatinine 1.6 mg/dL and total bilirubin 1.8 mg/dL). Liposomal clearances of the two drugs were highly correlated and 1000-fold smaller than published non-encapsulated values supporting prolonged encapsulation in the liposome. CONCLUSIONS: The PK model demonstrates prolonged exposure to cytarabine and daunorubicin without increases in non-hematologic toxicity that indicates retention of the drugs within the liposome. The unique pharmacology of this formulation may allow for simplified regimens and improved outcomes.
Authors: Bob Löwenberg; Thomas Pabst; Edo Vellenga; Wim van Putten; Harry C Schouten; Carlos Graux; Augustin Ferrant; Pieter Sonneveld; Bart J Biemond; Alois Gratwohl; Georgine E de Greef; Leo F Verdonck; Martijn R Schaafsma; Michael Gregor; Matthias Theobald; Urs Schanz; Johan Maertens; Gert J Ossenkoppele Journal: N Engl J Med Date: 2011-03-17 Impact factor: 91.245
Authors: Hugo F Fernandez; Zhuoxin Sun; Xiaopan Yao; Mark R Litzow; Selina M Luger; Elisabeth M Paietta; Janis Racevskis; Gordon W Dewald; Rhett P Ketterling; John M Bennett; Jacob M Rowe; Hillard M Lazarus; Martin S Tallman Journal: N Engl J Med Date: 2009-09-24 Impact factor: 91.245
Authors: E J Feldman; J E Kolitz; J M Trang; B D Liboiron; C E Swenson; M T Chiarella; L D Mayer; A C Louie; J E Lancet Journal: Leuk Res Date: 2012-07-26 Impact factor: 3.156
Authors: Jorge E Cortes; Stuart L Goldberg; Eric J Feldman; David A Rizzeri; Donna E Hogge; Melissa Larson; Arnaud Pigneux; Christian Recher; Gary Schiller; Krzysztof Warzocha; Hagop Kantarjian; Arthur C Louie; Jonathan E Kolitz Journal: Cancer Date: 2014-09-15 Impact factor: 6.860
Authors: Mario Luppi; Francesco Fabbiano; Giuseppe Visani; Giovanni Martinelli; Adriano Venditti Journal: Cancers (Basel) Date: 2018-11-09 Impact factor: 6.639
Authors: Victor U Weiss; Karin Wieland; Andreas Schwaighofer; Bernhard Lendl; Guenter Allmaier Journal: Anal Chem Date: 2019-02-27 Impact factor: 6.986