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A Pilot Study of Protracted Topotecan Dosing Using a Pharmacokinetically Guided Dosing Approach in Children with Solid Tumors¹

Departments of Hematology and Oncology [V. M. S., A. G.], Pharmaceutical Sciences [W. C. Z., M. N. K., C. F. S.], Biostatistics [M. T., T. L.], and Molecular Pharmacology [P. J. H.], St. Jude Children’s Research Hospital, and Departments of Pediatrics [V. M. S., A. G.] and Pharmacology [P. J. H.] and The Center for Pediatric Pharmacokinetics and Therapeutics [P. J. H., C. F. S.], University of Tennessee, Memphis, Tennessee 38103

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 x h (cohort 1) or 80–120 ng/ml x 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.

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