In Vivo and Ex Vivo Inhibition of Spinal Nerve Ligation-Induced Ectopic Activity by Sodium Channel Blockers Correlate to
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RESEARCH PAPER
In Vivo and Ex Vivo Inhibition of Spinal Nerve Ligation-Induced Ectopic Activity by Sodium Channel Blockers Correlate to In Vitro Inhibition of NaV1.7 and Clinical Efficacy: A PharmacokineticPharmacodynamic Translational Approach Ivana Kalezic & Lei Luo & Per-Eric Lund & Anders B Eriksson & Tjerk Bueters & Sandra A. G. Visser Received: 21 September 2012 / Accepted: 7 January 2013 / Published online: 1 February 2013 # Springer Science+Business Media New York 2013
ABSTRACT Purpose In vivo and ex vivo inhibition of ectopic activity of clinically used and newly developed sodium channel (NaV) blockers were quantified in the rat spinal nerve ligation (SNL) model using a pharmacokinetic-pharmacodynamic (PKPD) approach and correlated to in vitro NaV1.7 channel inhibition and clinical effective concentrations. Methods In vivo, drug exposure and inhibition of ectopic activity were assessed in anaesthetized SNL rats at two dose levels. Ex vivo, compounds were applied at increasing concentrations to dorsal root ganglias isolated from SNL rats. The inhibitory potency (IC50) was estimated using PKPD analysis. In vitro IC50 was estimated using an electrophysiology-based assay using recombinant rat and human NaV1.7 expressing HEK293 cells. Results In vivo and ex vivo inhibition of ectopic activity correlated well with the in vitro inhibition on the rat NaV1.7 channel. The estimated IC50s for inhibition of ectopic activity in the SNL model occurred at similar unbound concentrations as clinical effective concentrations in humans. Conclusions Inhibition of ectopic activity in the SNL model could be useful in predicting clinical effective concentrations for novel sodium channel blockers. In addition, in vitro potency could be used for screening, characterization and selection of compounds, thereby reducing the need for in vivo testing.
KEY WORDS ectopic activity . NaV1.7 . pharmacokinetics and pharmacodynamics . sodium channels . spinal nerve ligation rat model ABBREVIATIONS ACSF artificial cerebral spinal fluid Ce concentration in the biophase CIP congenital insensitivity to pain Cp concentration in plasma DRG dorsal root ganglion E effect at a certain concentration E0 baseline of effect Emax maximal attainable effect i.v intravenous IC50 concentration at which 50% inhibition is achieved keo rate constant between plasma and biophase concentration LC-MS/MS liquid chromatography with mass spectrometry detection n hill slope factor NaV voltage-gated sodium channel PKPD pharmacokinetic-pharmacodynamic SNL spinal nerve ligation
Electronic supplementary material The online version of this article (doi:10.1007/s11095-013-0979-6) contains supplementary material, which is available to authorized users. I. Kalezic : L. Luo : P.-E. Lund : A. B. Eriksson Neuroscience, CNSP Innovative Medicines AstraZeneca R&D S-151 85, Södertälje, Sweden T. Bueters DMPK, CNSP Innovative Medicines AstraZeneca R&D S-151 85, Södertälje, Sweden
S. A. G. Visser (*) Global DMPK, Centre of Excellence Innovative Medicines, AstraZeneca R&D SE-151 85, Sö
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