CPX-351 Population Pharmacokinetics in Patients with Hematologic Malignancies

CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, demonstrated significant survival benefit versus the conventional 7+3 regimen of cytarabine/daunorubicin in patients with secondary acute myeloid leukemia. A population pharmacokinetic (PK) analysis of total (ie, encapsulated + unencapsulated drug) plasma concentrations of cytarabine and daunorubicin following IV administration of CPX-351 assessed sources of variability in PK and determined if covariate-based dose adjustments may be warranted, particularly in patients with renal or hepatic impairment.

The PK population consisted of 195 patients with advanced hematologic malignancies. The median age was 67 years (range: 24-81) and body weight was 79.8 kg (range: 38.9-156.5). There were 119 (61.0%) male and 76 (39.0%) female patients, mainly of white race (84.6%). A total of 83 (42.6%) patients had normal renal function (creatinine clearance [CrCL] ≥90 mL/min), 83 (42.6%) had mild renal impairment (CrCL 60-89 mL/min), 28 (14.4%) had moderate renal impairment (CrCL 30-59 mL/min), and 1 (0.5%) had severe renal impairment (CrCL 15-29 mL/min). The majority (n = 179 [91.8%]) of patients had bilirubin <1.2 mg/dL; the rest (n = 16 [8.2%]) had bilirubin between 1.2-3 mg/dL. No patient had end-stage renal disease or bilirubin >3 mg/dL, as expected since these patients are not usually considered fit for intensive chemotherapy.

Nonlinear mixed-effect modeling was performed using NONMEM. Model evaluation and selection were assessed using a standard model discrimination process that included statistical criteria (eg, objective function value) and pertinent graphical representations of goodness-of-fit. Model validation/qualification was performed according to FDA and EMA guidelines for industry. Separate PK models were developed for cytarabine and daunorubicin, and intrinsic and extrinsic factors were evaluated as covariates. Intrinsic factors included body weight, body mass index, age, sex, race, white blood cell count, and markers of renal function (CrCL and serum creatinine) and hepatic function (bilirubin, aspartate and alanine aminotransferases, and alkaline phosphatase). The extrinsic factors were first dose amount, clinical study, and formulation.

The base PK models for cytarabine and daunorubicin used 2-compartment structural models, with drug input into the central compartment, first-order distribution between the central and peripheral compartments, and first-order elimination from the central compartment. Two-compartment structural models with body surface area (BSA) as an allometric scalar provided minimum bias in estimates of systemic clearance (CL) and volume of distribution for the central compartment (Vc).

Based on the final population PK model for cytarabine, a typical patient with BSA of 1.95 m² receiving 100 units/m² CPX-351 (100 mg/m² cytarabine + 44 mg/m² daunorubicin) is expected to have CL of 0.106 L/h with between-subject variability (BSV) of 70.5%, a Vc value of 5.12 L with BSV of 29.7%, and a peripheral volume of distribution (Vp) value of 0.214 L with BSV of 80.5%. Total volume of distribution (Vd = Vc + Vp) is predicted to be 5.33 L. The predicted half-lives associated with the distribution and elimination phases are 20.7 and 37.1 hours, respectively. The final population PK model for daunorubicin predicted a typical patient receiving the lyophilized formulation will have a CL value of 0.145 L/h with BSV of 49.4%, a Vc value of 4.34 L with BSV of 24.1%, and a Vp value of 0.523 L with BSV of 80.5%. Vd is predicted to be 4.86 L. The half-lives associated with the distribution and elimination phases are predicted to 11.1 and 26.2 hours, respectively.

All covariates were eventually excluded from the population PK models, except dose and formulation, which had a small effect on PK and are not expected to result in detectable changes in clinical safety or efficacy. The PK of total cytarabine and daunorubicin were unaltered in patients with mild or moderate renal impairment (30 mL/min ≤ CrCL ≤ 89 mL/min). The potential effects of severe renal impairment could not be determined. Furthermore, the PK of total cytarabine and daunorubicin were unaltered in patients with serum bilirubin ≤3 mg/dL. In conclusion, the results of the population PK analysis indicated that dose adjustments of CPX-351 are not warranted for mild or moderate renal impairment or serum bilirubin up to 3 mg/dL.