PharmD/PhD student Univ of Houston Coll of Pharmacy Houston, Texas, United States
Statement of Purpose: Spinal Cord Injury (SCI) is a devastating acute neurodegenerative condition. Pharmacological treatments so far offer minimal improvements in neurological and functional outcomes. Riluzole is indicated for the treatment of Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative disease, with extended survival time of 60 to 90 days, due to its neuroprotective activity. In this study, we evaluated the potential neural benefit of riluzole in patients with SCI by assessing the temporal improvements in motor outcomes.
Description of Methods & Materials: Patient data were collected from the Riluzole in Acute Spinal Cord Injury Study (RISCIS), a multi-center, randomized, placebo controlled, double-blinded, phase 2/3 clinical trial. Patients in the treatment group received a 100 mg of riluzole twice on day 1 as a loading dose, then 50 mg of riluzole twice daily for the rest of 13 days as a maintenance dose. Their plasma samples were drawn at 3 hours post dose and before the next dose, on days 3, 7, 10 and 14. Plasma samples were quantified using validated LC-MS/MS assay with LLOQ of 0.5 ng/ml. PK analysis was performed using Phoenix NLME version 8.2.
To examine therapeutic outcomes of riluzole, changes in Total Motor Score (TMS) were measured by International Standards for Neurological Classification of Spinal Cord Injury Examination (ISNCSCI) at baseline, 3 months and 6 months. Then, the differences in TMS between placebo and treated groups were analyzed by an unpaired t-test. Correlations between TMS changes in 6 months vs AUCD0-D14 and baseline TMS were also evaluated by 3-dimensional response surface methodology using Design Expert, version 9.
Data & Results: Twenty-nine SCI patients were enrolled in the PK sub-study of the trial (N=18 in placebo and N=11 in treatment groups). Most patients in both groups exhibited increases of TMS, characterized by natural recovery after spinal cord injury. However, changes in TMS within 6 months was greater at a mean of 35.63 with the riluzole treatment than the 20.80 in the placebo group. It is noteworthy that 5 out of 8 subjects (62.5%) in the treatment group showed increases of more than 30 points of TMS within the 6-month period compared to only 2 out of 10 subjects (20%) in the placebo group. Although our p-values were not desirable due to small sample size and two outliers in the placebo group, it is remarkable that more patients in the treatment group display clinically significant TMS improvements over the 6-month period. 3-dimensional response surface was derived to correlate the temporal recovery of motor functions and riluzole exposure (See Figure 1). TMS changes in 6 months were significantly correlated with the baseline TMS and AUCD0-D14 of riluzole, with P-value of 0.04. The red vertex of the quadratic surface indicates the optimal AUCD0-D14 within the range of 16-48 mg*h/ml at baseline TMS between 1 and 36.
Interpretation, Conclusion or Significance: Our study shows that riluzole may exert therapeutic effects on motor functions in SCI patients. TMS improvements were apparently greater with riluzole compared to placebo. This longitudinal neurological recovery was significantly correlated with the exposure to riluzole for 14-day treatment.
