Population Pharmacokinetic-Pharmacodynamic Modeling of Neutrophil and Platelet Count for Lower-Intensity Therapy of CPX-351 Combined with Venetoclax in Acute Myeloid Leukemia

Background:

Improved survival outcomes and a comparable safety profile with CPX-351 (a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio) vs conventional 7+3 chemotherapy in a pivotal phase 3 trial led to the approval of CPX-351 for newly diagnosed therapy-related acute myeloid leukemia (tAML) or AML with myelodysplasia-related changes (AML MRC) in adults and pediatric (aged ≥1 year) patients in the United States and in adults in Europe. The approved induction dose is 1-2 cycles of CPX-351 100 units/m² (daunorubicin 44 mg/m² and cytarabine 100 mg/m²) as a 90-minute intravenous infusion on days 1, 3, and 5 (days 1 and 3 for second induction). In this study, we developed a population pharmacokinetic-pharmacodynamic (PK‑PD) model of absolute neutrophil count (ANC) and platelet count to determine the optimal dose for a lower-intensity therapy (LiT) of CPX-351 combined with venetoclax.

Methods:

The CPX‐351 population PK-PD analysis was based on data collected from 3 clinical studies (phase 1 study [NCT00389428; J Clin Oncol 2011; 29(8):979-85]; phase 2 study [NCT02238925; Cancer Chemother Pharmacol 2019; 84(1):163-73]; phase 3 study [NCT01696084; J Clin Oncol 2018; 36(26):2684-92]) in patients with newly diagnosed high‐risk/secondary AML. Venetoclax population PK-PD analysis was based on data from a comprehensive safety analysis of venetoclax monotherapy (Clin Cancer Res 2018; 24(18):4371-9). ANC and platelet data used in the analysis were from 94 patients for CPX-351 and 272 patients for venetoclax.

Generalized semi-mechanistic population PK-PD analyses were performed using non-linear mixed‑effects modeling to characterize the time-course of ANC and platelet count following administration of CPX-351 and venetoclax monotherapy. The majority of system parameters were shared across the 2 therapies and a limited number of treatment-specific parameters were estimated by fitting CPX-351 and venetoclax PK time-courses simultaneously. An R Shiny app was developed for the simulation of different dosing regimens with favorable safety profiles to guide optimal dose selection for LiT of CPX-351 combined with venetoclax, assuming the 2 drug effects on ANC and platelet count were additive.

Results:

The generalized PK-PD model included multi-compartment transit models for ANC and platelet count with separate semi-mechanistic compartments to represent proliferating, maturing, and circulating cells. The model fitted CPX-351 and venetoclax PK-PD data with shared system parameters except for the drug-specific parameter IC₅₀ (concentration producing 50% of maximal inhibition of cell proliferation). For ANC, the estimated IC₅₀ values for CPX-351 and venetoclax were 295 μM (relative standard error [RSE]: 8.96%) and 120 μM (RSE: 18.0%), respectively; the shared mean transit time (MTT) estimate for ANC maturation was 66.6 h (RSE: 4.95%), and shared maximal inhibition of cell proliferation (I_max) was fixed to 1. For platelet count, the estimated IC₅₀ values for CPX-351 and venetoclax were 0.0109 μM (RSE: 50.2%) and 16.5 μM (RSE: 8.73%); the shared MTT estimate for platelet maturation was 87.2 h (RSE: 9.01%) and shared I_max estimate was 0.313 (RSE: 11.2%).

Simulations with different doses of CPX-351 in combination with 400 mg venetoclax were performed. The simulated mean nadir ANC were 2.1, 1.5, 1.1, and 0.6 × 10⁹/L for CPX-351 doses of 20, 40, 60, and 100 units/m², respectively, when administered on days 1 and 3 and combined with venetoclax 400 mg daily for 28 days. The simulated mean nadir platelet counts were 31.0, 30.3, 30.0, and 29.7 × 10⁹/L for CPX-351 doses of 20, 40, 60, and 100 units/m², respectively, when administered on days 1 and 3 and combined with venetoclax 400 mg daily for 28 days. Model-based simulated outcomes of ANC and platelet count were consistent with the observed trial data.

Conclusions:

A generalized semi-mechanistic population PK-PD model was developed to adequately describe the time-courses of ANC and platelet counts in patients with AML following the administration of CPX‑351 and venetoclax monotherapy and was used to infer the impact on ANC and platelet count when given in combination. Model-based simulations supported initial dose selection in the phase 1b study of combined CPX-351 LiT plus venetoclax as first-line treatment for patients with AML who are unfit for intensive chemotherapy (NCT04038437).