title: Escalating systemic exposure of continuous infusion topotecan in children with recurrent acute leukemia.
abstract: OBJECTIVE
  To determine the maximum-tolerated systemic exposure (MTSE) and exposure-limiting toxicity of continuous infusion topotecan in children with recurrent acute leukemia.
  
  
  METHODS
  Patients received escalating levels of topotecan systemic exposure as measured by steady-state topotecan lactone concentration (Css). Samples obtained within the first 24 hours were measured by high-pressure liquid chromatography (HPLC) for topotecan. A two-compartment model was fit to the data using a Bayesian algorithm. Css was calculated for each patient; if it differed by more than 20% of target, a new dosage was begun within 6 hours. Follow-up concentrations were obtained as well as serial plasma samples postinfusion. Toxicity and evidence of activity were assessed after each course.
  
  
  RESULTS
  Thirteen boys and five girls received 23 courses of topotecan. Target Css ranged from 1.0 to 5.3 ng/mL (topotecan doses, 0.5 to 3.3 mg/m2/d). Nineteen of 23 courses were within +/- 20% of target after adjustment (range, 77% to 139%). The MTSE was 4.0 ng/mL, and mucositis was exposure-limiting at 5.3 ng/mL. A significant relation between topotecan lactone Css and the severity of mucositis was observed. Myelosuppression was experienced but was not considered exposure-limiting. One complete response and one partial response were noted.
  
  
  CONCLUSIONS
  The MTSE for continuous infusion topotecan was 4.0 ng/mL. Responses were noted at Css comparable to those producing responses in a severe combined immunodeficiency (SCID) mouse model. Further studies of topotecan are warranted.
authors.affiliation: Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: Furman
authors.forename: S D
authors.initials: SD
authors.lastname: Baker
authors.forename: C B
authors.initials: CB
authors.lastname: Pratt
authors.forename: G K
authors.initials: GK
authors.lastname: Rivera
authors.forename: W E
authors.initials: WE
authors.lastname: Evans
authors.forename: C F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D012008:Recurrence; D019772:Topotecan
chemical_list: D000970:Antineoplastic Agents; D019772:Topotecan; D002166:Camptothecin