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

Doran, Angela C.; Osgood, Sarah M.; Mancuso, James P.; Shaffer, Christopher L.

doi:10.1124/dmd.112.046391

Cited by 40 publications

(46 citation statements)

References 37 publications

(59 reference statements)

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“…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.…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

Section: Pharmacokinetics Studiesmentioning

confidence: 99%

“…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).…”

Section: Pharmacokinetics Studiesmentioning

confidence: 99%

“…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.…”

Section: Pharmacokinetics Studiesmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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

Shaffer

Hurst

Scialis

et al. 2013

J Pharmacol Exp Ther

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a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) positive allosteric modulation (i.e., "potentiation") has been proposed to overcome cognitive impairments in schizophrenia, but AMPAR overstimulation can be excitotoxic. Thus, it is critical to define carefully a potentiator's mechanismbased therapeutic index (TI) and to determine confidently its translatability from rodents to higher-order species. Accordingly, the novel AMPAR potentiator N-{(3R,4S)-3-[4-(5-cyano-2-thienyl) phenyl]tetrahydro-2H-pyran-4-yl}propane-2-sulfonamide (PF-4778574) was characterized in a series of in vitro assays and single-dose animal studies evaluating AMPAR-mediated activities related to cognition and safety to afford an unbound brain compound concentration (C b,u )-normalized interspecies exposure-response relationship. Because it is unknown which AMPAR subtype(s) may be selectively potentiated for an optimal TI, PF-4778574 binding affinity and functional potency were determined in rodent tissues expected to express a native mixture of AMPAR subunits and their associated proteins to afford composite pharmacological values. Functional activity was also quantified in recombinant cell lines stably expressing human GluA2 flip or flop homotetramers. Procognitive effects of PF-4778574 were evaluated in both rat electrophysiological and nonhuman primate (nhp) behavioral models of pharmacologically induced N-methyl-D-aspartate receptor hypofunction. Safety studies assessed cerebellum-based AMPAR activation (mouse) and motor coordination disruptions (mouse, dog, and nhp), as well as convulsion (mouse, rat, and dog). The resulting empirically derived exposure-response continuum for PF-4778574 defines a single-dose-based TI of 8-to 16-fold for self-limiting tremor, a readily monitorable clinical adverse event. Importantly, the C b,u mediating each physiological effect were highly consistent across species, with efficacy and convulsion occurring at just fractions of the in vitro-derived pharmacological values.

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Section: Methodsmentioning

confidence: 99%

Section: Pharmacokinetics Studiesmentioning

confidence: 99%

Section: Pharmacokinetics Studiesmentioning

confidence: 99%

Section: Pharmacokinetics Studiesmentioning

confidence: 99%

mentioning

confidence: 99%

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