Rapid PK/PD Screening of a Novel Epilepsy Chemical Series
Background
The Scientific Team at Xyzagen was involved in supporting the in vivo medicinal chemistry screening for a client who was evaluating a new chemical series as a potential treatment for epilepsy. With Xyzagen’s fully integrated rodent pharmacokinetics and pharmacology capabilities we were able to understand the exposure response relationship of multiple chemical analogs within a chemical series in rapid order.
The Challenge
This client had identified a new chemical series of small molecules against a CNS target that was potentially relevant in the treatment of epilepsy and wanted to begin to understand which in vitro potent molecules were effective in vivo.
The Scientific Team at Xyzagen designed an in vivo screening program that was similar to the NIH NINDS ETSP with the addition of assessing plasma and brain concentrations levels after conducting the MES assay.
The Solution
Since the compounds were similar in structure, the bioanalytical group at Xyzagen designed a fit-for-purpose discovery bioanalytical LC/MS/MS method for rapid sample analysis of limited samples.
The method was a multiplexed mass spectrometer method for each batch of molecules, while the individual mouse samples were run separately. Two molecules from each batch screen were used as Internal Standards within the method.
The Results
After assessing the time to peak effect for the lead benchmark molecule within the series, the pharmacology/PK screen was set up to screen N=8 mice per compound. Mice were dosed either orally or intraperitoneally and their body temperature and rotarod performance were assessed prior to general behavior observations and the MES assay. Immediately post MES, mice were asphyxiated with CO2, and a terminal blood sample was collected for assessment of drug exposure in plasma. For select molecules that exhibited a pharmacological response or were very potent in vitro, exhibited plasma exposure but had no in vivo response, brains were collected to assess the potential for brain penetration.
Final Takeaway
The Xyzagen team was able to rapidly assess new chemical entities on a biweekly basis and screen through approximately fifty analogs and determine which chemical changes were providing a balance between in vitro potency and in vivo efficacy and systemic exposure. From this work, the client was able to identify chemical candidates for IND enabling toxicology and pharmacokinetic studies.
Learn how Xyzagen can help support your in vivo discovery PK/PD rodent candidate selection screens.
