PHARMACOKINETICS

Animals

Studies are conducted in adult male and female Sprague Dawley (SD) rats (Envigo) in an AAALAC-accredited facility with approval from an Institutional Animal Care and Use Committee, and implemented in accordance with the Guide for the Care and Use of Laboratory Animals 8th Edition (National Research Council, 2011) with standards set by the National Institutes of Health.

Study design

Pharmacokinetic (PK) studies are used to guide the selection of doses and route of administration and to determine the exposure levels of the asset over a time course in male and female rats, supporting subsequent behavioral studies. PK studies are designed to suit the specific asset and include evaluation of exposure in both plasma and brain in the tested formulation for determining CNS and peripheral drug exposures.

In most cases, two groups of animals are used in this evaluation. In one group of rats, blood is serially collected through jugular vein catheters (JVC) at several time points following administration of an asset (for example, 0.25, 0.5, 1, 2, 4, 6, and 24 hours after administration). Upon completion of the final serial collection, whole brains and trunk blood are collected from rats in that group. A second group of non-JVC rats can be used for whole brain and trunk blood collection at an additional timepoint if needed.

Plasma and brain samples are then prepared for bioanalysis with ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). All sample preparation parameters and UPLC-MS/MS conditions are designed specifically for the asset being analyzed. After the asset exposure levels are measured in plasma and brain samples, non-compartmental analyses are performed using gPKPDSim, a MATLAB-based graphical user interface (GUI) application (Hosseini et al., 2020) to determine the pharmacokinetic properties of the asset.

References

Hosseini I, Feigelman J, Gajjala A, Susilo M, Ramakrishnan V, Ramanujan S, Gadkar K. (2020). gQSPSim: a GUI application based on SimBiology® for standardized QSP model development and application. CPT Pharmacometrics Syst Pharmacol. 2020 Jan 19. PMID: 31957304 DOI: 0.1002/psp4.12494

National Research Council (2011). Guide for the Care and Use of Laboratory Animals: Eighth Edition. Washington, DC: The National Academies Press

This work was conducted by PsychoGenics Inc. (Paramus, NJ) in collaboration with PSPP, NINDS, NIH under contract # 75N95019D00026