DISPOSITION OF RECOMBINANT HUMAN GRANULOCYTE-COLONY-STIMULATING FACTOR IN CHILDREN WITH SEVERE CHRONIC NEUTROPENIA

The disposition of recombinant human granulocyte colony-stimulating factor (G-CSF) was studied in 11 children with severe chronic neutropenia given 6 to 48 mug G-CSF per kilogram subcutaneously. Serum concentrations of G-CSF were measured by bioassay. Peak serum G-CSF concentrations were proportional to dosage and occurred 2 to 8 hours after subcutaneous administration. Nine of the eleven children had a significant increase in absolute neutrophil count (ANC). The median ANC in responding patients was 6.7 X 10(9)/L on day 14 versus 0.17 X 10(9)/L on day 1 of therapy (p < 0.01). The G-CSF clearance increased as ANC increased, and the relationship was well described by a sigmoid model. Maximal clearance approached 2 ml/min per kilogram at ANCs > 17.0 X 10(9)/L; minimal clearance was 0.29 ml/min per kilogram at ANCs of 0. The half-life of G-CSF was inversely related to ANC; mean half-life was 4.7 hours at ANCs of 0 but < 2 hours of ANCs greater than 17.0 X 10(9)/L. The two patients who failed to achieve a clinical response had no change in G-CSF clearance or half-life, nor did they have an increase in ANC when G-CSF dosages were escalated to 18 or 48 mug/kg twice a day. These results indicate that G-CSF pharmacokinetics are directly influenced by ANC; higher serum concentrations, slower clearances, and longer half-lives are associated with low ANCs.