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Pharmacokinetics of subcutaneous recombinant human granulocyte colony-stimulating factor in children
N Stute1, V M Santana, J H Rodman
1Pharmaceutical Division, St Jude Children's Research Hospital, Memphis 38101.
Insights
Recombinant granulocyte colony-stimulating factor (rG-CSF) effectively maintains measurable levels in children with neuroblastoma after chemotherapy. Pharmacokinetics show dose-related exposure and increased clearance with higher neutrophil counts.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Hematology
Background:
- Neuroblastoma is a common pediatric cancer.
- Myelosuppressive chemotherapy is a standard treatment for advanced neuroblastoma.
- Granulocyte colony-stimulating factor (G-CSF) supports neutrophil recovery after chemotherapy.
Purpose of the Study:
- To evaluate the pharmacokinetics of recombinant G-CSF (rG-CSF) in children with advanced neuroblastoma.
- To assess the relationship between rG-CSF dose, serum concentrations, and absolute neutrophil count (ANC).
Main Methods:
- Fifteen children with advanced neuroblastoma received chemotherapy followed by 5, 10, or 15 µg/kg/day of rG-CSF subcutaneously for 10 days.
- Serum samples were analyzed for G-CSF activity using a proliferation assay.
- Pharmacokinetic parameters were determined using a one-compartment model.
Main Results:
- rG-CSF absorption was prolonged after subcutaneous injection, with peak concentrations reached in 4-12 hours.
- Measurable G-CSF levels were maintained throughout the 24-hour dosing interval.
- G-CSF clearance increased significantly by day 10 and correlated positively with ANC.
- Systemic exposure (AUC) was dose-related but showed interpatient variability.
- A predictive model for G-CSF AUC included rG-CSF dosage and ANC (R² = 0.82).
Conclusions:
- Subcutaneous rG-CSF provides sustained G-CSF levels in children undergoing chemotherapy for neuroblastoma.
- Pharmacokinetic parameters, including clearance and AUC, are influenced by rG-CSF dose and ANC.
- These findings support the use of rG-CSF to manage neutropenia in pediatric oncology patients.
Abstract:
Fifteen children (age 1.2 to 9.4 years) with advanced neuroblastoma were treated with myelosuppressive chemotherapy (cyclophosphamide, cisplatin, doxorubicin) followed by 5 (n = 5), 10 (n = 5), or 15 (n = 5) micrograms/kg recombinant granulocyte colony-stimulating factor (rG-CSF) subcutaneously (SC) once daily for 10 days, starting the day after chemotherapy. Serial serum samples obtained on days 1 and 10 were analyzed for G-CSF activity by a specific proliferation assay using NFS-60 cells. G-CSF serum concentration-time data were best described by a one-compartment model, with zero-order absorption and first-order elimination. After SC injection, absorption was prolonged, with peak concentrations of G-CSF (3 to 117 ng/mL) being reached after 4 to 12 hours. The relatively slow absorption, with a mean elimination half-life of 5.8 hours on day 1 and 4.5 hours on day 10, provided measurable G-CSF concentrations for the entire 24-hour dosing interval in all patients at each dosage level. The median apparent clearance of G-CSF on day 10 was significantly higher than on day 1 (0.57 v 0.31 mL/min/kg, P = .02), and was positively correlated with the absolute neutrophil count (ANC) (r2 = .33, P = .003). Systemic exposure to G-CSF was dose-related, but interpatient pharmacokinetic variability yielded overlap in area under the concentration-time curve (AUC) at all three dosage levels. Stepwise regression analysis showed that G-CSF AUC could be predicted by a model that includes rG-CSF dosage and ANC on the day of administration (r2 = .82, P = .0001).