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


METHODS
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/m(2) (range, 2.6-6) and 3 mg/m(2) (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/mm(3) 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.


CONCLUSIONS
Protracted topotecan dosing using a pharmacokinetic strategy was possible in this heavily pretreated group of children.
Santana
Victor M
VM
Department of Hematology, St. Jude Children's Research Hospital, University of Tennessee, Memphis, Tennessee 38103, USA.
Zamboni
William C
WC
Kirstein
Mark N
MN
Tan
Ming
M
Liu
Tiebin
T
Gajjar
Amar
A
Houghton
Peter J
PJ
Stewart
Clinton F
CF
D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016001:Confidence Intervals; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D010865:Pilot Projects; D019772:Topotecan / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D019772:Topotecan