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 Pharmacokinetic-Pharmacodynamic Translational Approach
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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.
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 (IC 50 ) was estimated using PKPD analysis. In vitro IC 50 was estimated using an electrophysiology-based assay using recombinant rat and human NaV1.7 expressing HEK293 cells.
In vivo and ex vivo inhibition of ectopic activity correlated well with the in vitro inhibition on the rat NaV1.7 channel. The estimated IC 50s for inhibition of ectopic activity in the SNL model occurred at similar unbound concentrations as clinical effective concentrations in humans.
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 WORDSectopic activity NaV1.7 pharmacokinetics and pharmacodynamics sodium channels spinal nerve ligation rat model
artificial cerebral spinal fluid
concentration in the biophase
congenital insensitivity to pain
concentration in plasma
dorsal root ganglion
effect at a certain concentration
baseline of effect
maximal attainable effect
concentration at which 50% inhibition is achieved
rate constant between plasma and biophase concentration
liquid chromatography with mass spectrometry detection
hill slope factor
voltage-gated sodium channel
spinal nerve ligation
Acknowledgments and Disclosures
The authors would like to thank Vibeke Täpp for technical help regarding the preparation of the animal model and Sveinn Briem and Yvonne Jaksch for their help with the bioanalysis of plasma and protein binding samples.
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