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

Abstract

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.

Fig. 1

Three-compartment model used for ventricular CSF modeling, in which K is an intercompartment rate constant and R_o is the infusion rate constant.

Fig. 2

Topotecan lactone concentration-versus-time plot. a. Before dosage adjustment (AUC = 30 ng/ml-h and vCSF exposure duration [---] ~ 4.8 h). b. After dosage adjustment (AUC = 135 ng/ml-h and vCSF exposure duration [---] > 8 h). Observed plasma (•) and CSF (▴) concentrations are plotted. The solid line represents best-fit plasma curve to last measured data point, and extrapolation is indicated by a dashed and dotted line. The dashed line represents best-fit vCSF curve to last measured data point, with extrapolation indicated by a dotted line. In both cases, extrapolation was achieved by simulation of concentration–time data using the estimated compartmental pharmacokinetic parameters. The bold horizontal dotted line represents the desired vCSF exposure duration of 1 ng/ml.

Fig. 3

Exposure duration versus targeted area under the concentration–time curve (AUC). Each line represents an individual study, and each symbol represents an individual patient. The dashed lines represent the studies that were removed in the subset analysis (patient 1). The bold horizontal line represents the EDT of 1 ng/ml for 8 h.

Fig. 4

Percent EDT versus targeted AUC. The bar represents the median, the boxes represent the quartiles, and whiskers represent the minimum and maximum. a. Full data set. b. Subset of data.