Monoclonal antibody exposure in rat and cynomolgus monkey cerebrospinal fluid following systemic administration View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-12

AUTHORS

Qin Wang, Luisette Delva, Paul H. Weinreb, Robert B. Pepinsky, Danielle Graham, Elvana Veizaj, Anne E. Cheung, Weiping Chen, Ivan Nestorov, Ellen Rohde, Robin Caputo, Geoffrey M. Kuesters, Tonika Bohnert, Liang-Shang Gan

ABSTRACT

BACKGROUND: Many 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. RESULTS: Upon intravenous (IV) bolus injection, antibodies entered the CNS slowly and reached maximum CSF concentration ( CSF T max ) in one to several days in both rats and monkeys. Antibody serum and CSF concentration-time curves converged until they became parallel after CSF T max was reached. Antibody half-lives in CSF ( CSF t ½ ) approximated their serum half-lives ( serum t ½ ). 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%. CONCLUSION: Upon systemic administration, average antibodies CSF-to-serum concentration ratios in rats and monkeys were 0.1-0.2%. The CSF t ½ of the antibodies was largely determined by their long systemic t ½ ( systemic t ½ ). More... »

PAGES

10

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s12987-018-0093-6

    DOI

    http://dx.doi.org/10.1186/s12987-018-0093-6

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1101633397

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29558954


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