Pharmacokinetics of sodium borocaptate: a critical assessment of dosing paradigms for boron neutron capture therapy.

The pharmacokinetics of sodium borocaptate (BSH), a drug that has been used clinically for boron neutron capture therapy (BNCT) of malignant brain tumors, have been characterized by measuring boron concentrations by direct current plasma-atomic emission spectroscopy (DCP-AES) in a group of 23 patients with high-grade gliomas. The disposition of BSH following intravenous (i.v.) infusion, which was determined by measuring plasma boron concentrations by DCP-AES, was consistent with a three-compartment open model with zero-order input and first-order elimination from the central compartment. Boron disposition was linear over the dose range of 26.5-88.2 mg BSH/kg body weight (b.w.), corresponding to 15-50 mg boron/kg b.w. Mean total body boron plasma clearance was 14.4 +/- 3.5 ml/min and the harmonic mean half-lives (range) were 0.6 (0.3-3.7), 6.5 (4.8-10.1) and 77.8 (49.6-172.0) h for the alpha, beta, and gamma disposition phases, respectively. Using an empirically determined plasma: blood boron concentration ratio of 1.3 +/- 0.2, the calculated total body boron blood clearance was 18.5 +/- 4.5 ml/min. In order to develop a model for selecting the optimum dosing paradigm, a pharmacokinetic correlation was established between the boron content of normal brain, solid tumor, and infiltrating tumor to the shallow tissue pharmacokinetic compartment (C2). Based on our model, it was concluded that although multiple i.v. infusions of BSH might increase absolute tumor boron concentrations, they will not improve the tumor: plasma boron concentration ratios over those attainable by a single i.v. infusion. The results from our study are confirmatory of those previously reported by others when blood sampling has been carried out for a sufficient period of time to adequately characterize the pharmacokinetics.