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.
OBJECTIVE
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 (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.


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 IC 50s 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.
Neuroscience, CNSP Innovative Medicines, AstraZeneca R&D, S-151 85, Södertälje, Sweden.
Ivana
I
Kalezic
Lei
L
Luo
Per-Eric
PE
Lund
Anders B
AB
Eriksson
Tjerk
T
Bueters
Sandra A G
SA
Visser
D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D008026:Ligation; D008297:Male; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009437:Neuralgia / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000097:blood* / Q000494:pharmacology*; D013127:Spinal Nerves / Q000187:drug effects* / Q000601:surgery
D062556:NAV1.7 Voltage-Gated Sodium Channel; C503480:Scn9a protein, rat; D026941:Sodium Channel Blockers