Cm. Kearns et al., DISPOSITION OF RECOMBINANT HUMAN GRANULOCYTE-COLONY-STIMULATING FACTOR IN CHILDREN WITH SEVERE CHRONIC NEUTROPENIA, The Journal of pediatrics, 123(3), 1993, pp. 471-479
The disposition of recombinant human granulocyte colony-stimulating fa
ctor (G-CSF) was studied in 11 children with severe chronic neutropeni
a given 6 to 48 mug G-CSF per kilogram subcutaneously. Serum concentra
tions of G-CSF were measured by bioassay. Peak serum G-CSF concentrati
ons were proportional to dosage and occurred 2 to 8 hours after subcut
aneous administration. Nine of the eleven children had a significant i
ncrease in absolute neutrophil count (ANC). The median ANC in respondi
ng 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; m
inimal clearance was 0.29 ml/min per kilogram at ANCs of 0. The half-l
ife of G-CSF was inversely related to ANC; mean half-life was 4.7 hour
s 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 i
n G-CSF clearance or half-life, nor did they have an increase in ANC w
hen 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 hal
f-lives are associated with low ANCs.