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.
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Acknowledgements
The phase 1 clinical trial was funded by Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals, plc. Dr. Nikanjam received salary support from a National Institutes of Health grant (4T32HL066992—Academic Training in Hematology) and a Tower Cancer Research Foundation Career Development Award. Additional funding support was provided by a Research in Pediatric and Developmental Pharmacology NIH Grant (1U54HD090259-01, Dr. Capparelli) and the Aramont Foundation for the study of Hematological Malignancies (Dr. Schiller).
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Dr. Capparelli serves on the data safety and monitoring board for Cempra Pharmaceuticals and The Medicines Company and has received consulting fees from Aptose, Plexxikon, Atox Bio Ltd, Celltrion, and Patara. Dr. Schiller has received research funding from Celator Pharmaceuticals. Dr. Louie is employed by Celator Pharmaceuticals.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Nikanjam, M., Capparelli, E.V., Lancet, J.E. et al. Persistent cytarabine and daunorubicin exposure after administration of novel liposomal formulation CPX-351: population pharmacokinetic assessment. Cancer Chemother Pharmacol 81, 171–178 (2018). https://doi.org/10.1007/s00280-017-3484-5
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DOI: https://doi.org/10.1007/s00280-017-3484-5