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 parameters were compared with respect to the patient's CDA status (i.e., Poor Metabolizer (PM) vs. Extensive Metabolizer (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 (T1/2 = 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 (T1/2: 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.