PhD defence

The LeiCNS-PK3.0 model development and applications: Healthy-to- diseased CNS pharmacokinetic translation

• M.A.A.E.W. Saleh

Date

Thursday 25 April 2024

Time

10:00 - 10:45 hour

Address

Academy Building
Rapenburg 73
2311 GJ Leiden

Supervisor(s)

• Prof.dr. E.C.M. de Lange

Summary

Neurological diseases are the principal cause of disability and the second main cause of death worldwide, accounting for about 10 million deaths each year. The development of new drugs to treat neurological disorders is a complex process and has suffered a high attrition rate of about 93%, which is the highest among the therapeutic indications. A large proportion of the failures has been attributed to the insufficient drug reaching the CNS. A key step towards the successful development and safe use of the CNS drugs is the assessment of how much drug would eventually reach the CNS and how this quantity changes over time, i.e. pharmacokinetic (PK) profile. We have developed the LeiCNS-PK3.0 CNS mathematical model, which could predict adequately the amount of drug that reaches the brain and cerebrospinal fluid (CSF) of rats, mice, and humans. Based on our model simulations, we have shown the importance of PK assessment of the CNS target site(s) in the brain and that lumbar CSF PK profiles cannot be considered as accurate surrogates of those of the brain. Furthermore, we highlighted the importance of accounting comprehensively for the changes of the CNS physiology during healthy aging and in CNS diseases for accurate predictions of the brain and CSF PK profiles. Altogether, our work highlighted key lessons on CNS pharmacokinetics that seem relevant to streamline and optimize CNS drug research and development.

PhD dissertations

Approximately one week after the defence, PhD dissertations by Leiden PhD students are available digitally through the Leiden Repository, that offers free access to these PhD dissertations. Please note that in some cases a dissertation may be under embargo temporarily and access to its full-text version will only be granted later.

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