title: Disposition of recombinant human granulocyte colony-stimulating factor in children with severe chronic neutropenia.
abstract: The disposition of recombinant human granulocyte colony-stimulating factor (G-CSF) was studied in 11 children with severe chronic neutropenia given 6 to 48 micrograms 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 at 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 micrograms/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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38101.
authors.forename: C M
authors.initials: CM
authors.lastname: Kearns
authors.forename: W C
authors.initials: WC
authors.lastname: Wang
authors.forename: N
authors.initials: N
authors.lastname: Stute
authors.forename: J N
authors.initials: JN
authors.lastname: Ihle
authors.forename: W E
authors.initials: WE
authors.lastname: Evans
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009503:Neutropenia / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor