Longitudinal Impact of Acute Spinal Cord Injury on Clinical Pharmacokinetics of Riluzole, a Potential Neuroprotective Agent

Riluzole, a benzothiazole sodium channel blocker that received US Food and Drug Administration approval to attenuate neurodegeneration in amyotrophic lateral sclerosis in 1995, was found to be safe and potentially efficacious in a spinal cord injury (SCI) population, as evident in a phase I clinical...

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Published inJournal of clinical pharmacology Vol. 61; no. 9; pp. 1232 - 1242
Main Authors Nguyen, Ashley, Chow, Diana S‐L., Wu, Lei, Teng, Yang (Angela), Sarkar, Mahua, Toups, Elizabeth G., Harrop, James S., Schmitt, Karl M., Johnson, Michele M., Guest, James D., Aarabi, Bizhan, Shaffrey, Christopher I., Boakye, Maxwell, Frankowski, Ralph F., Fehlings, Michael G., Grossman, Robert G.
Format Journal Article
LanguageEnglish
Published England 01.09.2021
Subjects
Clinical Trials, Phase I as Topic
Dose-Response Relationship, Drug
Double-Blind Method
Half-Life
Humans
Metabolic Clearance Rate
Models, Biological
Neuroprotective Agents - pharmacokinetics
Neuroprotective Agents - therapeutic use
pharmacokinetics
population modeling
riluzole
Riluzole - pharmacokinetics
Riluzole - therapeutic use
Spinal Cord Injuries - drug therapy
spinal cord injury
Time Factors
spinal cord injury
pharmacokinetics
population modeling
riluzole
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Summary:Riluzole, a benzothiazole sodium channel blocker that received US Food and Drug Administration approval to attenuate neurodegeneration in amyotrophic lateral sclerosis in 1995, was found to be safe and potentially efficacious in a spinal cord injury (SCI) population, as evident in a phase I clinical trial. The acute and progressive nature of traumatic SCI and the complexity of secondary injury processes can alter the pharmacokinetics of therapeutics. A 1‐compartment with first‐order elimination population pharmacokinetic model for riluzole incorporating time‐dependent clearance and volume of distribution was developed from combined data of the phase 1 and the ongoing phase 2/3 trials. This change in therapeutic exposure may lead to a biased estimate of the exposure‐response relationship when evaluating therapeutic effects. With the developed model, a rational, optimal dosing scheme can be designed with time‐dependent modification that preserves the required therapeutic exposure of riluzole.
ISSN:0091-2700
1552-4604
DOI:10.1002/jcph.1876