for Dose-dependent Plasma Clearance of Thiotepa Cerebrospinal Fluid and Plasma of Pediatric Patients: Evidence Phase I and Pharmacokinetic Evaluation of Thiotepa in the

ABSTRACTA Phase I trial of thiotepa (II) administered as an i.v. bolus wasperformed in 19 children with refractory malignancies. The starting dosewas 25 mg/m2with escalations to 50, 65, and 75 mg/nr. Seven additionalpatients were treated with 8-h infusions at 50 or 65 mg/m2.The maximumtolerated bolus dose was 65 mg/m2. Reversible myelosuppression was thedose-limiting toxicity.The plasma and cerebrospinal fluid (CSF) pharmacokinetic parameters of TT and its major active metabolite tepa (TP) were also evaluated.When the bolus or infusion methods of TT administration were compared,there was little difference observed in any pharmacokinetic parameterfor either TT or TP. The plasma disappearance of TT was rapid andbiphasic with half-lives of 0.14 to 0.32 and 1.34 to 2.0 h. Dose-dependentpharmacokinetics was demonstrated by steadily declining plasma clearance with increasing TT dose. Clearance values declined from 28.6 liters/m2/h at the 25-mg/m2 dose to 11.9 liters/mz/h at the 75-mg/m2 dose.The half-life of TP was longer than that of TT and ranged between4.3 and 5.6 h. There was evidence of the saturation of TP production.TT and TP both exhibited excellent penetration into the CSF, producing lumbar and ventricular concentrations which were nearly identical tosimultaneous plasma concentrations. In one patient with a Rickhamreservoir, the CSF:plasma area under the (concentration x time) curveratios for TT and TP were 1.01 and 0.95, respectively.The above data indicate that TT can be safely administered to pediatriepatients at doses higher than conventionally used. The favorable CSFpenetration of TT and TP suggests that Phase II studies of TT beconsidered in patients with central nervous system tumors.INTRODUCTIONTT2 is a polyfunctional alkylating agent which has been inclinical use for more than 30 yr. It is currently used i.v. in adultoncology for the treatment of ovarian and breast cancer, as wellas being administered intravesically for the treatment of bladdercancer, and intrathecally for meningeal carcinomatosis. In addition, high-dose TT has been used as preparative chemotherapy for autologous bone marrow transplantation in patientswith refractory malignancies (1-5). The observation that TTdisplays excellent CSF penetration in the nonhuman primatefollowing i.v administration suggests that TT may also be ofsome clinical utility in the treatment of central nervous systemmalignancies (6).In vivo, TT is metabolized to TP, a molecule which retainsTT's three aziridine rings and is itself a potent alkylator (Fig.1). Although recent publications have described the human