Population Pharmacokinetics and Exposure‐Response Analyses for CPX‐351 in Patients With Hematologic Malignancies

Abstract

CPX‐351, a dual‐drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, is approved in the United States for adults with newly diagnosed therapy‐related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia‐related changes. Population pharmacokinetics analyses were performed using nonlinear mixed‐effect modeling on pooled data from 3 clinical studies, and the impact of CPX‐351 exposures on efficacy and safety was assessed. The pharmacokinetics of cytarabine and daunorubicin were described using 2‐compartment models with linear elimination. None of the evaluated covariates had a clinically significant impact on plasma exposure to total cytarabine or daunorubicin, while bilirubin and formulation showed statistically significant effects on pharmacokinetic parameters of cytarabine and daunorubicin, respectively. In patients with mild/moderate renal impairment or serum bilirubin ≤3 mg/dL, plasma exposures to cytarabine and daunorubicin following CPX‐351 were within the variability range for patients with normal kidney function or serum bilirubin levels. Exposure‐response analysis demonstrated that better efficacy outcomes were associated with higher CPX‐351 exposure quartiles. Early mortality rates in all CPX‐351 exposure quartiles were lower vs the 7 + 3 control group, and lower mortality rates were associated with higher exposure quartiles. A trend toward greater frequency of grade 3 treatment‐emergent adverse events (but not grade 4/5 events) was observed at higher CPX‐351 exposure quartiles. Overall, the population pharmacokinetic analyses indicate no adjustments to the recommended dose and schedule of CPX‐351 are warranted for patients with mild/moderate renal impairment or serum bilirubin ≤3 mg/dL. Results from the exposure‐response analyses suggest the current CPX‐351 regimen provides a favorable risk‐benefit profile.

Sequentially Site‐Specific Delivery of Apoptotic Protein and Tumor‐Suppressor Gene for Combination Cancer Therapy

“…To address this issue, nanocarrier‐based systems for codelivery of multiple drugs have increasingly been empoldered to offer a spatio‐temporal unification of separate pharmacokinetics of different drug payloads, which are evidenced to be more effective in preclinical and clinical studies . For instance, Vyxeos, a liposomal preparation coloaded with cytarabine and daunorubicin (5:1 molar ratio), has been approved by the U.S. Food and Drug Administration for acute myeloid leukemia treatment . Vyxeos can maintain a constant 5:1 drug ratio in the plasma of patients for up to 24 h after intravenous administration, which shows significantly enhanced anticancer efficacy with prolonged survival period compared with the conventional cocktail of cytarabine and daunorubicin (7:3 molar ratio) …”

CPX-351 Pharmacokinetics and Safety in Adults with Hematologic Malignancies and Renal Function Impairment: Phase 1 Trial

“…These results are supported by a previous population PK analysis comparing exposures of CPX-351 in patients with hematologic malignancies with mild and moderate renal impairment vs. normal renal function. Wang et al reported a similar mean AUC tau between patients with normal renal function and mild/moderate renal impairment for daunorubicin and cytarabine in an analysis of data collected from three clinical studies of patients with advanced hematologic malignancies, AML or acute lymphocytic leukemia, and newly diagnosed high-risk/secondary AML [ 18 ].…”

“…Previously, the results of a population pharmacokinetic (PK) analysis indicated that no dose adjustments of CPX-351 were needed for patients with hematologic malignancies and mild/moderate renal impairment [ 18 ]. However, the effect of severe renal impairment on the PK and side effect profile of CPX-351 has not been established.…”