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Pharmacokinetics of O⁶-benzylguanine in Pediatric Patients with Central Nervous System Tumors

A Pediatric Oncology Group Study

¹ Department of Pediatrics, Baylor College of Medicine, Houston, Texas;
² Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, Canada; and
³ University of Vermont College of Medicine, Burlington, Vermont

Purpose: To report the results of the first pharmacokinetic study in pediatric patients of O⁶-benzylguanine (O⁶BG), which irreversibly inactivates the DNA repair protein alkylguanine-alkyltransferase, thus enhancing the cytotoxicity of nitrosoureas.

Experimental Design: As part of a Pediatric Oncology Group Phase I study, 120 mg/m² of O⁶BG was administered i.v. over 1 h, before 1,3-bis(2-chloroethyl)-1-nitrosourea administration in children with recurrent or refractory brain tumors. Serial blood samples for plasma pharmacokinetic studies were obtained. Concentrations of O⁶BG and its active metabolite O⁶-benzyl-8-oxoguanine (8-oxo-O⁶BG) were measured by high-performance liquid chromatography. A pharmacokinetic model and additional first-order elimination rate constants for each compound were developed.

Results: O⁶BG concentration versus time data were evaluated for 25 patients. The peak concentration of O⁶BG (mean ± SD) was 11 ± 4 µM, and the peak concentration of its active metabolite, 8-oxo-O⁶BG, was 35 ± 10 µM. O⁶BG was rapidly eliminated with a half-life of 85 ± 140 min, area under the curve of 795 ± 320 µM · min and clearance of 760 ± 400 ml/min/m². The area under the curve of 8-oxo-O⁶BG when extrapolated to infinity was 22,700 ± 11,800 µM · min. The clearance and terminal half-life of 8-oxo-O⁶BG were 30 ± 15 ml/min/m² and 360 ± 220 min, respectively.

Conclusions: There is rapid elimination of O⁶BG after i.v. administration over 1 h. In contrast, the terminal half-life for the active metabolite, 8-oxo-O⁶BG, is 4-fold longer. The pharmacokinetic parameters for O⁶BG and 8-oxo-O⁶BG are similar to those reported previously in adults.