Pharmacology of riluzole in acute spinal cord injury.
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2012-09
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The aim of this paper was to characterize individual and population pharmacokinetics of enterally administered riluzole in a Phase 1 clinical trial of riluzole as a neuroprotective agent in adults 18-70 years old with acute spinal cord injury (SCI).Methods
Thirty-five individuals with acute SCI, American Spinal Injury Association Impairment Scale Grades A-C, neurological levels from C-4 to T-12, who were enrolled in the Phase 1 clinical trial sponsored by the North American Clinical Trials Network for Treatment of Spinal Cord Injury, received 50 mg riluzole twice daily for 28 doses. The first dose was administered at a mean of 8.7 ± 2.2 hours postinjury. Trough plasma samples were collected within 1 hour predose, and peak plasma samples were collected 2 hours postdose on Days 3 and 14 of treatment. Riluzole concentrations were quantified by high-performance liquid chromatography assay. The data were analyzed for individual and population pharmacokinetics using basic structural and covariate models. The pharmacokinetic measures studied were the peak concentration (C(max)), trough concentration (C(min)), systemic exposure (AUC(0-12)), clearance (CL/F), and volume of distribution (V_F) normalized by the bioavailability (F).Results
The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher CL and larger V. The pharmacokinetics of riluzole (C(max), C(min), AUC(0-12), CL, and V) changed during the acute and subacute phases of SCI during the 14 days of therapy. It was consistently observed in patients at all clinical sites that C(max), C(min), and AUC(0-12) (128.9 ng/ml, 45.6 ng/ml, and 982.0 ng × hr/ml, respectively) were significantly higher on Day 3 than on Day 14 (76.5 ng/ml, 19.1 ng/ml, and 521.0 ng × hr/ml, respectively). These changes resulted from lower CL (49.5 vs 106.2 L/hour) and smaller V (557.1 vs 1297.9/L) on Day 3. No fluid imbalance or cytochrome P 1A2 induction due to concomitant medications was identified during the treatment course to account for such increases in V and CL, respectively. Possible mechanisms underlying these changes are discussed.Conclusions
This is the first report of clinical pharmacokinetics of riluzole in patients with SCI. The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher clearance and larger volume of distribution in SCI patients. The finding in SCI patients of an increase in the clearance and distribution of riluzole between the 3rd and 14th days after SCI, with a lower plasma concentration of riluzole on the 14th day, stresses the importance of monitoring changes in drug metabolism after SCI in interpreting the safety and efficacy of therapeutic drugs that are used in clinical trials in SCI. Clinical trial registration no.: NCT00876889.Type
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Chow, Diana SL, Yang Teng, Elizabeth G Toups, Bizhan Aarabi, James S Harrop, Christopher I Shaffrey, Michele M Johnson, Maxwell Boakye, et al. (2012). Pharmacology of riluzole in acute spinal cord injury. Journal of neurosurgery. Spine, 17(1 Suppl). pp. 129–140. 10.3171/2012.5.aospine12112 Retrieved from https://hdl.handle.net/10161/28874.
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Christopher Ignatius Shaffrey
I have more than 25 years of experience treating patients of all ages with spinal disorders. I have had an interest in the management of spinal disorders since starting my medical education. I performed residencies in both orthopaedic surgery and neurosurgery to gain a comprehensive understanding of the entire range of spinal disorders. My goal has been to find innovative ways to manage the range of spinal conditions, straightforward to complex. I have a focus on managing patients with complex spinal disorders. My patient evaluation and management philosophy is to provide engaged, compassionate care that focuses on providing the simplest and least aggressive treatment option for a particular condition. In many cases, non-operative treatment options exist to improve a patient’s symptoms. I have been actively engaged in clinical research to find the best ways to manage spinal disorders in order to achieve better results with fewer complications.
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