Pharmacokinetics And Safety Of Pegylated Recombinant Human Granulocyte Colony-Stimulating Factor In Children With Acute Leukemia

BackgroundNeutropenic complications remain the primary dose-limiting adverse events of cytotoxic chemotherapeutic drugs and tumor-targeted drugs.Febrile neutropenia(FN)usually requires hospitalization and the empiric use of broad-spectrum antibiotics.The risk of mortality associated with FN remains relatively high due to complications such as infection and sepsis.Dose reduction,delay,or even cancellation of chemotherapy that follows FN’s occurrence may have a life-threatening impact on disease control of malignant tumors that may be responsive and potentially curable.Therefore,prevention or treatment of neutropenia is essential to ensure adequate or dose-intensive chemotherapy.Pegylated recombinant human granulocyte colony-stimulating factor(PEG-rhG-CSF)and recombinant human granulocyte colony-stimulating factor(rhG-CSF)are effective drugs for the prevention and treatment of chemotherapy-induced neutropenia in patients with malignant tumors.PEG-rhG-CSF has a long half-life and increases absolute neutrophil count after a single subcutaneous injection.PEG-rhG-CSF has more sustained effects on granulopoiesis and stronger biostability,shortening the duration of chemotherapy-induced neutropenia.Only a single administration per cycle of chemotherapy is acquired,thus reducing the number of injections,improving patient compliance,and effectively guaranteeing the implementation of full dose and full course of the chemotherapy regimen.A single subcutaneous PEG-rhG-CSF dose has demonstrated efficacy by reducing the incidence of febrile neutropenia and shortening the duration of severe neutropenia and was well tolerated,comparable to daily subcutaneous doses of rhG-CSF.However,the safety and efficacy of PEG-rhG-CSF have mostly been demonstrated in pediatric patients receiving cytotoxic chemotherapy for solid tumors.Clinically,PEG-rhG-CSF has been used to support neutrophil recovery after myelosuppressive chemotherapy in pediatric leukemia patients,but its efficacy and safety remain unclear.Meanwhile,a limited number of studies have evaluated the pharmacokinetics of PEG-rhG-CSF in pediatric patients with sarcoma,and no data are available in pediatric patients with acute leukemia.AimThis open-label,prospective,phase Ⅰ study was designed to preliminarily assess the pharmacokinetics and safety of PEG-rhG-CSF treating chemotherapy-induced neutropenia in pediatric patients with acute leukemia.MethodsPEG-rhG-CSF was administered as a single 100 mcg/kg(3 mg maximum dose)subcutaneous injection at the end of each chemotherapy period when neutropenia occurred.Blood samples were obtained from patients treated with PEG-rhG-CSF.PEG-rhG-CSF serum concentrations were determined by an enzyme-linked immunosorbent assay(ELISA).Population pharmacokinetic(PPK)analysis was implemented using the nonlinear mixed-effects model.Short-term safety was evaluated through adverse events collection.This study was registered in www.clinicaltrials.gov as#NCT03844360.ResultsA total of 16 acute leukemia patients(1.8-13.6 years)were included,of whom 2(12.5%)had grade 3 neutropenia,6(37.5%)had grade 4 neutropenia,and 8(50.0%)had severe neutropenia.For PPK modeling,64 PEG-rhG-CSF serum concentrations were obtainable.A one-compartment model with first-order elimination was used for pharmacokinetic data modeling.The current weight was a significant covariate.The median(range)of CL and AUC were 5.65(1.49-14.45)mL/h/kg and 16514.75(6632.45-54423.30)ng·h/mL,respectively.Bone pain,pyrexia,anaphylaxis,and nephrotoxicity were not observed.One patient died 13 days after administration,and the objective assessment of causality was that an association with PEG-rhG-CSF was"possible" according to the Naranjo Scale.ConclusionThe AUC of PEG-rhG-CSF(100 mcg/kg,3 mg maximum dose)in pediatric patients with acute leukemia were similar to those of PEG-rhG-CSF(100 mcg/kg)in children with sarcoma.PEG-rhG-CSF is safe and provides an important therapeutic option for chemotherapy-induced neutropenia in pediatric patients with acute leukemia.It will support the pediatric trial design of PEG-rhG-CSF in the following phases of the pediatric drug development plan.