Effect of radiation on the penetration of irinotecan in rat cerebrospinal fluid

Abstract

Anticancer agents are useful for treating brain tumors, but sub therapeutic concentrations due to decreased blood-brain barrier (BBB) penetration limit their effectiveness. This study evaluated the effect of cranial radiation on the pharmacokinetics of irinotecan in plasma and cerebrospinal fluid (CSF). Rats (n = 48) were treated with irinotecan (10 mg/kg), and then administered 10 or 20 Gy or sham irradiation as control after drug. The pharmacokinetics for irinotecan, SN-38, and APC were measured in plasma and CSF over 6 h. Up to 7 plasma samples per animal were collected, and one CSF sample was collected per animal (serial sacrifice design). Population pharmacokinetic analysis was performed with NONMEM, and radiation tested as a covariate for the fraction of irinotecan (f(CSF)) entering the CSF. The estimate of f(CSF) (% and RSE) was 0.165 (73.5) for the control group and 0.265 (66.5) for radiation-treated groups, respectively (P < 0.05). Predictive check plots showed that the model adequately described the overall trend and variability in the observed data. The median values of bootstrap parameters were similar to the NONMEM estimates based on the original data set. These results indicate that cranially administered radiation can increase the penetration of anticancer agents such as irinotecan into the CSF. Studies that evaluate radiation-fractionation, radiation-time course effect relationships, blood-brain barrier and blood-tumor barrier effects for irinotecan and other anticancer agents are warranted.