PHARMACOKINETICS OF RECOMBINANT HUMAN GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR IN CHILDREN AFTER INTRAVENOUS AND SUBCUTANEOUS ADMINISTRATION

Despite its widespread use, only limited pharmacokinetic data exist fo r recombinant human granulocyte-macrophage colony-stimulating factor ( rhGM-CSF), especially in children. We evaluated the pharmacokinetics o f rhGM-CSF in children who had undergone intensive multiagent chemothe rapy: 11 children with refractory solid tumors received 500-1500 mu g/ m(2) of rhGM-CSF (sargramostim) as a daily 2-h intravenous (iv) infusi on, and seven children received subcutaneous (sc) rhGM-CSF at 1500-200 0 mu g/m(2)/d in two daily injections for 2 weeks. Serum samples obtai ned before and after rhGM-CSF administration were analyzed for granulo cyte-macrophage colony-stimulating factor (GM-CSF) by a bioassay and b y ELISA. Concentrations measured by the two methods were highly correl ated (r(2) = 0.89, p < 0.001). Following 2-h iv infusions, the concent ration-time data were best described by a two-compartment, first-order elimination model. The median (range) for rhGM-CSF systemic clearance (Cl) was 49 mL/min/m(2) (range, 15-118 mL/min/m(2)), terminal half-li fe (fm) was 1.6 h (range, 0.9-2.5 h), and the time the GM-CSF concentr ation was >1 ng/mL was 9 h (range, 6-13 h). The CI was not dose depend ent or related to patient age. The absolute neutrophil count day 14 of GM-CSF was significantly related to GM-CSF dosage and platelet count on day 1. There was a weak correlation between AUG and duration of neu tropenia (p = 0.05). The sc concentration-time data were best describe d by a one-compartment model with first-order absorption and eliminati on. Median apparent clearance was 72 mL/min/ m(2) (range, 27-231 mL/mi n/m(2)) and t(1/2) was 2.3 h (range 0.7-3.8 h). Absorption was prolong ed, with peak concentrations reached after 3 h (range, 1.5-4 h), and m odel-estimated median time the GM-CSF concentrations was >1 ng/mL was >26 h. These data establish comparable pharmacokinetic characteristics of rhGM-CSF in children and adults, supporting single daily sc dosing in both age groups.