A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors

Purpose: To assess the use of a pharmacokinetically guided topotecan strategy and evaluate the toxicity of protracted i.v. topotecan in children with recurrent solid tumors. Experimental design: Fifteen children with measurable relapsed or refractory solid tumors received topotecan i.v. over 30 min 5 days a week for two consecutive weeks. Doses were individualized based on the patient's topotecan systemic clearance to attain a single day topotecan lactone area under the plasma concentration time curve (AUC) of 120-180 ng/ml × h (cohort 1) or 80-120 ng/ml × h (cohort 2). Clinical responses and toxicity were assessed by standard criteria. Results: Twenty-nine courses of topotecan were administered, 11 in cohort 1 and 18 in cohort 2. The median topotecan dosages required to achieve the target AUCs for cohorts 1 and 2 were 4 mg/m² (range, 2.6-6) and 3 mg/m² (range, 2.6-4.2), respectively. The intersubject variance for topotecan clearance exceeded the intrasubject variance by 2-fold. With the pharmacokinetic targeting approach, we observed that 78% (46 of 59) of the measured AUC values were within the target range. The median number of days to an absolute neutrophil count ≥500/mm³ was similar between the two cohorts; however, febrile neutropenia and serious infections limited our ability to deliver drug dosages needed to secure the higher systemic exposure (cohort 1). Five partial responses were observed. Conclusion: Protracted topotecan dosing using a pharmacokinetic strategy was possible in this heavily pretreated group of children.