Abstract
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).
Highlights
The blood brain barrier (BBB) is the single most significant obstacle that impedes the delivery of therapeutics to targets in the central nervous system (CNS)
We report the kinetic relationships of cerebrospinal fluid (CSF) versus serum concentration–time profiles of five humanized monoclonal antibodies in rats and cynomolgus monkeys following systemic administration and factors that affect their CSF antibody exposures
The pharmacokinetic properties of five human antibodies in serum and CSF were evaluated in rats and non-human primate (NHP)
Summary
The blood brain barrier (BBB) is the single most significant obstacle that impedes the delivery of therapeutics to targets in the central nervous system (CNS). We report the kinetic relationships of CSF versus serum concentration–time profiles of five humanized monoclonal antibodies in rats and cynomolgus monkeys following systemic administration and factors that affect their CSF antibody exposures. These findings have important implications for assessing CNS antibody drug kinetics in humans. Cerebrospinal fluid (CSF) sampling is routinely used as a surrogate for assessing CNS drug exposure and biomarker levels. 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
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