Clinical pharmacodynamics of continuous infusion topotecan in children: systemic exposure predicts hematologic toxicity.
OBJECTIVE
Topotecan pharmacokinetics and pharmacodynamics were studied following a 72-hour continuous infusion in 20 children with cancer (median age, 8 years; range, 3.5 to 18).


METHODS
Serial plasma and urine samples were collected during the infusion and for up to 6 hours following the end of infusion. Topotecan (lactone) and total (lactone plus hydroxy acid) concentrations were determined by a sensitive and specific high-performance liquid chromatography (HPLC) assay with fluorescence detection. Using maximum a posteriori-Bayesian modeling, lactone and total plasma concentrations were described separately by a two-compartment model. Hematologic toxicity was expressed as the percent decrease in absolute neutrophil count (ANC) and platelet count. The relation between systemic exposure (SE) and hematologic toxicity was modeled using a sigmoid maximum-effect model.


RESULTS
Systemic clearance rates for lactone and total topotecan were (mean +/- SD) 18.5 +/- 7.0 and 6.5 +/- 2.4 L/h/m2, respectively. Urinary recovery of total topotecan was (mean +/- SD) 67.5% +/- 25.2% (n = 12 patients). SE (area under the concentration-time curve from zero to infinity [AUC] or steady-state plasma concentration [Cpss]) to either topotecan lactone or total topotecan was significantly correlated to hematologic toxicity (P < .05). Overall, patients with a higher SE to topotecan experienced greater hematologic toxicity.


CONCLUSIONS
These data demonstrate a relation between systemic exposure to topotecan and clinical effect (myelosuppression). Moreover, these data provide the basis for development of individualized topotecan administration schedules.
Stewart
C F
CF
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38101-0318.
Baker
S D
SD
Heideman
R L
RL
Jones
D
D
Crom
W R
WR
Pratt
C B
CB
D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D007783:Lactones / Q000493:pharmacokinetics; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D009504:Neutrophils; D010976:Platelet Count / Q000187:drug effects; D019772:Topotecan
D000970:Antineoplastic Agents; D007783:Lactones; D019772:Topotecan; D002166:Camptothecin