© Copyright 2006 by the Society for Neuro-Oncology
Received March 16, 2005
Accepted September 21, 2005
Basic and Translational Investigations
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Using plasma topotecan pharmacokinetics to estimate
topotecan exposure in cerebrospinal fluid of children with
medulloblastoma
Clinton F. Stewart 1*,
Lisa C. Iacono 2,
John C. Panetta 3,
Amar Gajjar 4,
Burgess B. Freeman III 2
1 Department of Pharmaceutical Sciences, St. Jude
Children's Research Hospital and Department of Pediatrics, College of
Medicine, University of Tennessee
2 Department of Pharmaceutical Sciences, St. Jude
Children's Research Hospital
3 Department of Pharmaceutical Sciences, St. Jude
Children's Research Hospital, Memphis, and University of
Tennessee
4 Division of Neuro-Oncology, Department of
Hematology--Oncology, St. Jude Children's Research Hospital, and
Department of Pediatrics, College of Medicine, University of
Tennessee
* To whom correspondence should be addressed. E-mail: clinton.stewart{at}stjude.org.
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Abstract |
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The purpose of this study was to estimate ventricular
cerebrospinal fluid (vCSF) topotecan lactone (TPT) exposures in pediatric
medulloblastoma patients from plasma concentration-time data by using a
pharmacokinetic (PK) model. We studied children with high-risk
medulloblastoma who received pharmacokinetically guided TPT (target plasma
area under the concentration-time curve [AUC], 120--160 ng/ml-h) and
obtained serial vCSF samples to assess TPT exposure. Population
pharmacokinetic parameters were determined by using linear mixed-effects
modeling via the two-stage approach. We simulated TPT vCSF exposure
duration at plasma TPT AUC values of 120 to 200 ng/ml-h and determined
percentages of studies meeting or exceeding the vCSF exposure duration
threshold (EDT) of 1 ng/ml for 8 h. We then used bootstrap methods to
estimate variability in vCSF EDT. Eighteen PK studies were conducted in
six patients (median age, 4.8 years). In these patients, seven of nine
studies attaining target plasma TPT AUC achieved the vCSF EDT. Given a
plasma TPT AUC of 120 ng/ml-h, the median percentage of results meeting or
exceeding EDT was 78% (95% CI, 61%--100%). One patient (four studies) with
tumor blockage of CSF flow, which can alter CSF pharmacokinetics, was
removed, and the bootstrap analysis was repeated. In this subset, a median
93% (95% CI, 79%--100%) of studies achieved vCSF EDT. Increasing plasma TPT
AUC values resulted in increased ability to achieve vCSF EDT. We
demonstrated that a plasma PK model could estimate vCSF TPT
concentrations. Further, our results indicate that the TPT vCSF EDT can be
achieved in more than 80% of studies targeted to a plasma TPT AUC of 120
ng/ml-h.
Key Words:
children, cerebrospinal fluid, pharmacokinetics, topotecan
