Pharmacokinetics of CPX-351; a nano-scale liposomal fixed molar ratio formulation of cytarabine:daunorubicin, in patients with advanced leukemia

Forty-eight patients received CPX-351 (liposome-encapsulated cytarabine:daunorubicin at a 5:1 molar ratio) every other day for 3 doses at 10 dose levels. Pharmacokinetic parameters were dose-independent and exhibited low inter-patient variability. CPX-351 showed a negligible distribution phase and prolonged mono-exponential first-order plasma elimination (t1/2 ∼ 24 h). The plasma ratio of 5:1 was maintained at all dose levels. Nearly all of the detectable cytarabine and daunorubicin in circulation following CPX-351 administration was in the form of liposome encapsulated drug. Dose-dependent hematopoietic effects had early onset with cytopenias at 12 units/m2, and a gradual increase in frequency and severity, until single induction complete response was achieved at 43 units/m2. Non-hematologic effects had onset by 24 units/m2 with shallow dose-response until maximum frequency and severity were observed at the 101-134 units/m2 dose levels. Single induction response occurred over a 2.3-fold range of doses indicating that CPX-351 may be useful at high doses for patients suitable for intensive chemotherapy and at reduced doses for patients at increased risk of treatment-related mortality. The unique pharmacologic features of CPX-351 contribute to its promising antileukemic efficacy.