Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351

JOURNAL OF CONTROLLED RELEASE

卷:338

Article

Donnette, Melanie^1,2,3,4  Hamimed, Mourad^1,3,4  Ciccolini, Joseph^1,2,3,4  Berda-Haddad, Yael⁵  Kaspi, Elise⁶  Venton, Geoffroy⁷  Lacarelle, Bruno^1,2,3,4  Costello, Regis⁷  Ouafik, L''Houcine⁸  Farnault, Laure⁷  Fanciullino, Raphaelle^1,3,4,9 

[1] Aix Marseille Univ, CRCM Inserm U1068, SMARTc, Marseille, France

[2] La Timone Univ Hosp Marseille, Clin Pharmacokinet Lab, Marseille, France

[3] Aix Marseille Univ, COMPO CRCM Inserm U1068, CNRS, UMR 7258, Marseille, France

[4] INRIA, Ctr Rech Sophia Mediterranee, Rocquencourt, France

[5] La Conception Univ Hosp Marseille, Hematol Lab, Marseille, France

[6] AixMarseille Univ, Hosp Timone, AP HM, Celle Biol Unit, Marseille, France

[7] La Conception Univ Hosp Marseille, Hematol Oncol Unit, Marseille, France

[8] Nord Univ Hosp Marseille, Transfert Oncol Lab, Marseille, France

[9] La Conception Univ Hosp Marseille, Pharm, Marseille, France

关键词: Liposomal cytarabine;    Cytidine deaminase;    Pharmacokinetics;    Drug release;    Modeling;   

DOI  :  10.1016/j.jconrel.2021.08.023

来源: Elsevier

【 摘 要 】

CPX-351 is a liposome encapsulating cytarabine and daunorubicin for treating Acute Myeloid Leukemia (AML) patients. To what extent differences in cytidine deaminase (CDA) activity, the enzyme that catabolizes free cytarabine in the liver, can affect the pharmacokinetics of liposomal cytarabine as well, is unknown. We have studied the pharmacokinetics (PK) of released, liposomal and total cytarabine using a population-modeling approach in 9 adult AML patients treated with liposomal CPX-351. Exposure levels and PK parame-ters were compared with respect to the patient's CDA status (i.e., Poor Metabolizer (PM) vs. Extensive Metab-olizer (EM)). Overall response rate was 75%, and 56% of patients had non-hematological severe toxicities, including one lethal toxicity. All patients had febrile neutropenia. A large (>60%) inter-individual variability was observed on pharmacokinetics parameters and subsequent drug levels. A trend towards severe toxicities was observed in patients with higher exposure of cytarabine. Results showed that liposomal CPX-351 led to sustained exposure with reduced clearance (Cl = 0.16 L/h) and prolonged half-life (T-1/2 = 28 h). Liposomal nanoparticles were observed transiently in bone marrow with cytarabine levels 2.3-time higher than in plasma. Seven out of 9 patients were PM with a strong impact on the PK parameters, i.e., PM patients showing higher cytarabine levels as compared with EM patients (AUC: 5536 vs. 1784 ng/mL.h), sustained plasma exposure (T-1/2: 33.9 vs. 13.7 h), and reduced clearance (Cl: 0.12 vs. 0.29 L/h). This proof-of-concept study suggests that CDA status has a major impact on cytarabine PK and possibly safety in AML patients even when administered as a liposome.

【 授权许可】

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