Persistent cytarabine and daunorubicin exposure after administration of novel liposomal formulation CPX-351: population pharmacokinetic assessment.

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/m). 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.