Abstract
To date, no drug therapy has shown significant efficacy in improving functional outcomes in patients with acute spinal cord injury (SCI). Riluzole, an FDA approved sodium channel blocker to attenuate neurodegeneration in amyotrophic lateral sclerosis (ALS), is of interest for neuroprotection in SCI. In a Phase I clinical trial (ClinicalTrials.gov Identifier: NCT00876889), riluzole was well tolerated with a 2-week treatment at the dose level approved for ALS and exhibited potential efficacy in SCI patients. The acute and progressive nature of traumatic SCI and the complexed secondary injury processes alter the pharmacokinetics (PK) of therapeutics. In the PK Sub-study of the multicenter, randomized, placebo-controlled, double-blinded RISCIS Phase II/III trial (ClinicalTrials.gov Identifier: NCT01597518), 32 SCI patients were enrolled, mostly middle-aged Caucasian males with head and neck injuries. PK and pharmacodynamics (PD) of riluzole on motor recovery, were measured by ISNCSCI Motor Score at injury, 3-month and 6-month follow-ups, and axonal injury biomarker, phosphorylated neurofilament heavy chain (pNF-H), during the two-week treatment. PK modeling, PK/PD correlations were developed to identify the potential effective exposure of riluzole for intended PD outcomes. The longitudinal impacts of SCI on the PK of riluzole are characterized. A time-varying population PK model of riluzole is established, incorporating time-varying clearance and volume of distribution from combined data of Phase I and Phase II/III trials. With the model, a rational dosing scheme can be designed with time-dependent modification to preserve the required therapeutic exposure of riluzole. The PD of riluzole of neurological outcomes and PK/PD correlation of the treatment were established. The time courses of efficacy in total motor score improvement (∆TMS) and pNF-H were monitored. A 3D PK/PD correlation was established for ∆TMS at 6 months with overall riluzole exposure, AUCD0-D14, and baseline TMS for individual patients. Patients with baseline TMS of 1 and 36 benefited from the optimal exposure range of 16 - 48 mg*h/ml. The PD models of pNF-H revealed the riluzole efficacy, with diminished increase in progression of pNF-H, indicative of reduced axonal breakdown. The independent parameter of Area Between Effective Curves (ABEC) of pNF-H in placebo and treatment groups was statistically identified as a significant predictor for the treatment effect. A mechanistic CO (Clinical Outcomes)/PD (pNF-H) model was established, and the proposed structure demonstrated the feasibility of PK/PD/CO correlation model. No appreciable hepatic toxicity was observed with the current riluzole treatment regimen. The development of effective treatment for SCI is challenging. However, the future model-informed and PK-guided drug development and regimen modification can be rationally executed with the optimal dosing regimen design based on the 3D PK/PD model. The PK/PD/CO model can serve as a rational guide for future drug development, PKPD model refinement, and extension to other studies in SCI settings.
