Using plasma topotecan pharmacokinetics to estimate topotecan exposure in cerebrospinal fluid of children with medulloblastoma1

摘要

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 pharmaco‐kinetic (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.