Clinical pharmacodynamics of continuous infusion topotecan in children: systemic exposure predicts hematologic toxicity.

Abstract

PURPOSE 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. CONCLUSION 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.