Pharmacokinetics of O(6)-benzylguanine in pediatric patients with central nervous system tumors: a pediatric oncology group study.

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. Serial 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 microm, and the peak concentration of its active metabolite, 8-oxo-O(6)BG, was 35 +/- 10 microm. O(6)BG was rapidly eliminated with a half-life of 85 +/- 140 min, area under the curve of 795 +/- 320 microm. 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 microm. 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 half-life 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.

Plasma and cerebrospinal fluid pharmacokinetics of imatinib after administration to nonhuman primates.

PURPOSE: Imatinib mesylate (Gleevec, Glivec, STI571, imatinib) is a potent tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. The role of imatinib in the treatment of malignant gliomas and other solid tumors is being evaluated. We used a nonhuman primate model that is highly predictive of the cerebrospinal fluid penetration of drugs in humans to study the pharmacokinetics of imatinib in plasma and cerebrospinal fluid (CSF) after i.v. and p.o. administration. EXPERIMENTAL DESIGN: Imatinib, 15 mg/kg i.v. over 30 min (n = 3) or 30 mg/kg p.o. (n = 3), was administered to nonhuman primates. Imatinib was measured in serial samples of plasma and CSF using high-pressure liquid chromatography with UV absorbance or mass spectroscopic detection. Pharmacokinetic parameters were estimated using model-independent methods. RESULTS: Peak plasma imatinib concentrations ranged from 6.4 to 9.5 microM after i.v. dosing and 0.8 to 2.8 microM after p.o. dosing. The mean +/-SD area under the plasma concentration versus time curve was 2480 +/-1340 microM.min and 1191 +/-146 microM.min after i.v. and p.o. dosing, respectively. The terminal half-life was 529 +/-167 min after i.v. dosing and 266 +/-88 min after p.o. dosing. After i.v. dosing the steady state volume of distribution was 5.9 +/-2.8 liter/kg, and the total body clearance was 12 +/-5 ml/min/kg. The mean peak CSF concentration was 0.25 +/-0.07 microM after i.v. dosing and 0.07 +/-0.04 microM after p.o. dosing. The mean CSF:plasma area under the plasma concentration versus time curve ratio for all of the animals was 5% +/-2%. CONCLUSIONS: There is limited penetration of imatinib into the CSF of nonhuman primates after i.v. and p.o. administration.

Plasma and cerebrospinal fluid pharmacokinetics of rebeccamycin (NSC 655649) in nonhuman primates.

PURPOSE: The rebeccamycins, indolocarbazole topoisomerase I poisons originally discovered in actinomycetes, have shown activity in vitro against a range of adult and pediatric tumors. The derivative NSC 655649 (diethylaminoethyl analog of rebeccamycin, or DEAE rebeccamycin) is currently undergoing early-phase human studies and has shown some signs of antitumor activity. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of NSC 655649 after systemic administration in a nonhuman primate model that is predictive of anticancer drug behavior in humans. DESIGN: A dose of 400 mg/m2 was infused over 1 h to three rhesus monkeys. Serial blood and CSF samples were collected. Rebeccamycin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic analysis was performed using compartmental and noncompartmental methods. RESULTS: A two-compartment or three-compartment model described rebeccamycin pharmacokinetics in plasma adequately. In two animals, the three-compartment model provided a better fit, and in one animal, the two-compartment model was better. The terminal half-life was 730+/-410 min, the AUC was 3130+/-425 microM min, and the clearance was 190+/-25 ml/min/m2. Rebeccamycin was below the limit of quantitation in all CSF samples. The animals had some nausea and agitation during and shortly after the infusion that responded to treatment with prochlorperazine or diazepam. Otherwise, rebeccamycin was well tolerated with minimal toxicity. CONCLUSION: Rebeccamycin penetrates poorly into the CSF following an intravenous infusion. Therefore, systemically administered rebeccamycin is unlikely to be an important agent for the treatment of leptomeningeal tumors. Because the drug is associated with local irritation at injection sites, it is not an ideal candidate for development as an intrathecal agent. However, the role of rebeccamycin in the treatment of parenchymal brain tumors should be determined in clinical trials.

Plasma and cerebrospinal fluid pharmacokinetics of SU5416 after intravenous administration in nonhuman primates.

PURPOSE: SU5416 is a small, lipophilic synthetic molecule that selectively inhibits the tyrosine kinase activity of the VEGF receptor Flk-1/KDR. The role of this agent in brain tumors is currently being investigated. Pharmacokinetic studies of SU5416 have been performed in humans; however, there have been no studies of its penetration in the cerebrospinal fluid (CSF). We studied the pharmacokinetics of SU5416 in plasma and CSF after intravenous (i.v.) administration using a nonhuman primate model that is highly predictive of the CSF penetration in humans. EXPERIMENTAL DESIGN: SU5416 (85 mg/m(2), about 3.8 mg/kg) was administered i.v. over 20 min to four nonhuman primates. Serial plasma and CSF samples were obtained prior to, during, and after completion of the infusion for determination of SU5416 concentrations. SU5416 was measured in plasma and CSF using high-performance liquid chromatography (HPLC). Concentration-versus-time data were modeled using model-independent and model-dependent methods. RESULTS: Peak plasma concentrations ranged from 6.3 to 14.5 microM and the mean plasma AUC was 620+/-180 microM.min. Disappearance of SU5416 from the plasma was best described by a one-compartment model with a half-life of 39+/-2.9 min. The volume of distribution was 36+/-11 l/m(2) and the clearance was 0.62+/-0.2 l/min per m(2). SU4516 was not quantifiable in the CSF. CONCLUSIONS: There is minimal penetration of SU5416 into the CSF after i.v. administration. The very low CNS exposure to SU5416 after i.v. dosing suggests that this agent is not optimal for the treatment of leptomeningeal tumors.

Plasma and cerebrospinal fluid pharmacokinetic study of BNP1350 in nonhuman primates.

PURPOSE: BNP1350 (7-[(2-trimethylsilyl)ethyl]-20(S)-camptothecin, karenitecin), a highly lipophilic camptothecin, a high percentage of which is maintained in the active lactone form under physiologic conditions, has recently entered clinical trials in adults and children. BNP1350 has shown significant preclinical antitumor activity against a wide variety of adult and pediatric tumor cell lines. This study was undertaken to define the pharmacokinetics of BNP1350 in both plasma and cerebrospinal fluid (CSF) in a nonhuman primate model. METHODS: Four nonhuman primates with indwelling Ommaya reservoirs received BNP1350, 0.1 mg/kg i.v, administered as a 60-min infusion. Frequent plasma and CSF samples were obtained for quantitation of BNP1350 concentrations using reverse-phase high-pressure liquid chromatography (HPLC). RESULTS: Disappearance of the lactone form from the plasma was biexponential with a mean distribution half-life of 57.5 min (CV +/-33%) and an elimination half-life of 457 min (CV +/-24%). The volume of distribution for the central compartment was 1.36 l/kg (CV +/-27%) and clearance from the central compartment was 10.6 ml/kg per minute (CV +/-28%). The peripheral compartment volume of distribution was 1.96 l/kg (CV +/-8.4%). Peak CSF lactone concentration, which occurred at 12 to 25 min after the end of the infusion, was 0.33 n M (CV +/-71%). CONCLUSIONS: The ratio of the CSF AUC to the plasma AUC was less than 5% (range 0.4% to 3.0%), similar to other highly protein-bound topoisomerase inhibitors such as 9-aminocamptothecin and SN-38 (the active metabolite of irinotecan).