An Evaluation of Using Rat-Derived Single-Dose Neuropharmacokinetic Parameters to Project Accurately Large Animal Unbound Brain Drug Concentrations

Abstract

ABSTRACT:Previous publications suggest that interstitial fluid compound concentrations (C ISF ) best determine quantitative neurotherapeutic pharmacology relationships, although confirming large animal C ISF remains elusive. Therefore, this work primarily evaluated using respective acute dose, rat-derived unbound brain compound concentration-to-unbound plasma compound concentration ratios (C b,u / C p,u ) to project accurately dog and nonhuman primate (nhp) C b,u , a C ISF surrogate, from measured C p,u for the highly permeable non-Pglycoprotein substrates N-{(3R,4S)-3-[4-(5-cyano-2-thienyl)phenyl]tetrahydro-2H-pyran-4-yl}propane-2-sulfonamide (PF-4778574) and [4-chloro-5-fluoro-2-(3-methoxy-2-methyl-phenoxy)-benzyl]-methylamine (CE-

Positive Allosteric Modulation of AMPA Receptors from Efficacy to Toxicity: The Interspecies Exposure-Response Continuum of the Novel Potentiator PF-4778574

“…All animal studies were performed in accordance with the Guide for the Care and Use of Laboratory Animals using protocols reviewed and approved by the WRD Institutional Animal Care and Use Committee. All blood samples were collected in EDTA-containing tubes and processed immediately to obtain plasma, and the collection of neuromatrices from rodents followed published techniques (Doran et al, 2012). All biomatrices collected for PF-4778574 quantification were stored at 270°C until processing for bioanalysis.…”

“…Plasma and Brain Homogenate Nonspecific Binding Using a reported (Doran et al, 2012) equilibrium dialysis procedure, the unbound fraction of PF-4778574 (1 mM, N 5 3/species) in plasma (f u,p ) and in brain homogenate (f u,b ) were determined. The stability of PF-4778574 in each matrix and the optimal dialysis time were determined separately prior to actual studies.…”

“…As described (Doran et al, 2012), a single dose (1 mg/kg, s.c.) of PF-4778574 in 2:98 (v/v) DMSO:20% hydroxypropyl-b-cyclodextrin (1 mg/ml) was injected (1 ml/kg) into each male Sprague-Dawley rat. Blood, cerebrospinal fluid (CSF), and brain samples were collected from each animal after euthanasia by CO 2 asphyxiation at 0.25, 0.5, 1, 2, 4, and 8 hours after dose (N 5 2/time point).…”

“…Quantitative Analysis of PF-4778574 in Biologic Matrices The quantification of PF-4778574 in plasma, CSF, or brain tissue samples from rodents, dogs, or nhp was achieved using published liquid chromatography-tandem mass spectrometry methodologies (Doran et al, 2012). The dynamic ranges were 0.488-500 ng/ml for plasma samples and 0.488-1000 ng/ml for CSF and brain tissue samples.…”

“…1) (Estep et al, 2008). This exposure-response approach is grounded in both the "free drug" hypothesis (Tillement et al, 1988), which stipulates that interstitial fluid potentiator concentrations dictate its interaction with the extracellular ligand binding domains of AMPARs (Shaffer, 2010), and the unbound brain compound concentration (C b,u ) being a valid interstitial fluid potentiator concentration surrogate Doran et al, 2012).…”