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Pharmaceutical Research

, Volume 30, Issue 5, pp 1409–1422 | Cite as

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

  • Ivana Kalezic
  • Lei Luo
  • Per-Eric Lund
  • Anders B Eriksson
  • Tjerk Bueters
  • Sandra A. G. Visser
Research Paper

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 (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.

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

Notes

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.

Supplementary material

11095_2013_979_MOESM1_ESM.jpg (709 kb)
Figure S1 In vivo electrophysiology observations for all non-selective sodium channel blockers tested. Left panels: Observed and fitted plasma concentrations in a simultaneous analysis with additional intravenous PK data (data not shown). Middle panels: observed and simultaneously fitted time-course of the inhibition of ectopic activity at two dose levels. Right panels: the relationship between the biophase concentration and the observed and predicted inhibition of ectopic activity. (JPEG 708 kb)
11095_2013_979_MOESM2_ESM.jpg (647 kb)
Figure S2 In vivo electrophysiology observations for newly developed sodium channel blockers tested. Left panels: Observed and fitted plasma concentrations in a simultaneous analysis with additional intravenous PK data (data not shown). Middle panels: observed and simultaneously fitted time-course of the inhibition of ectopic activity at two dose levels. Right panels: the relationship between the biophase concentration and the observed and predicted inhibition of ectopic activity. (JPEG 647 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Ivana Kalezic
    • 1
  • Lei Luo
    • 1
  • Per-Eric Lund
    • 1
  • Anders B Eriksson
    • 1
  • Tjerk Bueters
    • 2
  • Sandra A. G. Visser
    • 3
  1. 1.Neuroscience, CNSP Innovative MedicinesAstraZeneca R&DSödertäljeSweden
  2. 2.DMPK, CNSP Innovative MedicinesAstraZeneca R&DSödertäljeSweden
  3. 3.Global DMPK, Centre of Excellence Innovative MedicinesAstraZeneca R&DSödertäljeSweden

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