Pharmacokinetics of O6-benzylguanine in Pediatric Patients with Central Nervous System Tumors: A Pediatric Oncology Group Study

K. Neville
2004 Clinical Cancer Research  
Purpose: To report the results of the first pharmacokinetic study in pediatric patients of O 6 -benzylguanine (O 6 BG), 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/m 2 of O 6 BG was administered i.v. over 1 h, before 1,3-bis(2-chloroethyl)-1-nitrosourea administration in children with recurrent or refractory brain tumors.
more » ... l blood samples for plasma pharmacokinetic studies were obtained. Concentrations of O 6 BG and its active metabolite O 6 -benzyl-8-oxoguanine ( 8-oxo-O 6 BG) were measured by high-performance liquid chromatography. A pharmacokinetic model and additional first-order elimination rate constants for each compound were developed. Results: O 6 BG concentration versus time data were evaluated for 25 patients. The peak concentration of O 6 BG (mean ؎ SD) was 11 ؎ 4 M, and the peak concentration of its active metabolite, 8-oxo-O 6 BG, was 35 ؎ 10 M. O 6 BG was rapidly eliminated with a half-life of 85 ؎ 140 min, area under the curve of 795 ؎ 320 M ⅐ min and clearance of 760 ؎ 400 ml/min/m 2 . The area under the curve of 8-oxo-O 6 BG when extrapolated to infinity was 22,700 ؎ 11,800 M ⅐ min. The clearance and terminal half-life of 8-oxo-O 6 BG were 30 ؎ 15 ml/min/m 2 and 360 ؎ 220 min, respectively. Conclusions: There is rapid elimination of O 6 BG after i.v. administration over 1 h. In contrast, the terminal halflife for the active metabolite, 8-oxo-O 6 BG, is 4-fold longer. The pharmacokinetic parameters for O 6 BG and 8-oxo-O 6 BG are similar to those reported previously in adults.
doi:10.1158/1078-0432.ccr-03-0123 pmid:15297409 fatcat:hgbxkok7brdenh4m6efyasaace