Model-Based Evaluation Of Pegfilgrastim Effects On Chemotherapy-Induced Neutropenia In Infants With Cns Tumors.

Abstract Pegfilgrastim (PG), a pegylated recombinant form of human granulocyte colony-stimulating factor (G-CSF), is used to shorten the duration of chemotherapy-induced neutropenia. Previous studies have characterized the neutrophil response to PG exposure in adults, but little information is available for the infant population (<1-year-old). This study aims to develop a pharmacokinetic/pharmacodynamic (PK/PD) model to characterize PG PK, the chemotherapy-induced neutropenia, and the neutrophil response to PG in infants and young children with brain tumors. PG concentration-time data and absolute neutrophil counts (ANC) were obtained from 21 children including 13 infants (median [range] age 0.96 [0.4-2.9] years) with newly diagnosed atypical teratoid rhabdoid tumors, enrolled in a phase 2 study (NCT02114229). Patients received multiple cycles of age- and risk-adapted chemotherapy. A single dose of 100 µg/kg PG was given SC 24-48h after the last doses of chemotherapy of each cycle, i.e., cisplatin 75 mg/m2 and high-dose cyclophosphamide (CTX) 1.5 g/m2. A total of 37 PG PK studies were performed for up to 12 days post-dose, and serum PG concentrations were analyzed using a validated ELISA test, with a limit of quantification of 39 pg/mL. The ANC was monitored routinely throughout the cycles. Population PK/PD modeling was performed using Monolix 2019R2. The model included four components: PG PK, neutrophil dynamics, CTX PK, and endogenous G-CSF dynamics. PG data were adequately described with a one-compartment model with linear delayed absorption, and dual linear ANC-dependent and saturable non-specific elimination processes. CTX-induced neutropenia was well captured with a classic myelosuppression model, in which PG and endogenous G-CSF stimulated the neutrophil proliferation and maturation. PG concentrations were inversely correlated with ANC. Median (range) PG AUC0-∞ was 39,917 (7,233-66,410) h·ng/mL, with no significant differences between infants and older children. The ANC profiles exhibited pre-nadir peaks higher than post-nadir peaks, which was captured by the model with the addition of transit compartments to include a delay in the chemotherapy effect. The ANC nadir was reached 7.0±1.1 days post-CTX dose and was below 10 cells/mm3 for 88% of patients. The ANC recovered above 500 cells/mm3 13.4±4.0 days post-CTX dose. PG effects were described using concentration-dependent slopes (mean 0.089 and 0.044 per ng/mL for stimulation of neutrophil proliferation and maturation, respectively). No association was found between patient age and PG effects. Further investigations will be performed to explore the effects of patient covariates, ANC baseline before treatment, and timing of PG administration. As such, the model may be a useful tool for optimization of chemotherapy and PG treatment to minimize the risk of severe neutropenia occurring in infants and young children. Citation Format: Olivia Campagne, Abigail Davis, Santhosh A. Upadhyaya, Clinton F. Stewart. Model-based evaluation of pegfilgrastim effects on chemotherapy-induced neutropenia in infants with CNS tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1358.