BackgroundMany studies have focused on the challenges of small molecule uptake across the blood–brain barrier, whereas few in-depth studies have assessed the challenges with the uptake of antibodies into the central nervous system (CNS). In drug development, cerebrospinal fluid (CSF) sampling is routinely used as a surrogate for assessing CNS drug exposure and biomarker levels. In this report, we have studied the kinetic correlation between CSF and serum drug concentration–time profiles for five humanized monoclonal antibodies in rats and cynomolgus monkeys and analyzed factors that affect their CSF exposure.ResultsUpon intravenous (IV) bolus injection, antibodies entered the CNS slowly and reached maximum CSF concentration (CSFTmax) in one to several days in both rats and monkeys. Antibody serum and CSF concentration–time curves converged until they became parallel after CSFTmax was reached. Antibody half-lives in CSF (CSFt½) approximated their serum half-lives (serumt½). Although the intended targets of these antibodies were different, the steady-state CSF to serum concentration ratios were similar at 0.1–0.2% in both species. Independent of antibody target and serum concentration, CSF-to-serum concentration ratios for individual monkeys ranged by up to tenfold from 0.03 to 0.3%.ConclusionUpon systemic administration, average antibodies CSF-to-serum concentration ratios in rats and monkeys were 0.1–0.2%. The CSFt½ of the antibodies was largely determined by their long systemic t½ (systemict½).

ABSTRACT:The objectives of the study were to characterize the selectivity of dantrolene to breast cancer resistance protein (Bcrp) and to evaluate whether cerebrospinal fluid (CSF) can be used as a surrogate to assess brain exposures of BCRP and P-glycoprotein (

The improved system presented herein further streamlines the bioanalytical workflow, simplifies batch run design, reduces analyst intervention and eliminates sample-handling error.

The use of a nonstandard photocuring technique can produce noticeably improved results: POLICRYPS optimally verifies this condition. Originally being invented as a tunable diffractive structure, POLICRYPS has rapidly attracted much attention for its excellent morphology and related peculiar features. Low light scattering, low switching voltages and short switching times qualify POLICRYPS as a suitable platform for the realization of several applications.