Impacts of Spinal Cord Injury and Formulation on Riluzole Pharmacokinetics and Pharmacokinetics/Pharmacodynamics (PK/PD) Correlation

dc.creatorTeng, Yang 1982- 2012 2012
dc.description.abstractAcute Spinal Cord injury (SCI) is a complex disorder involving a sudden traumatic insult to the cord resulting in deficits to ambulatory, sensory and autonomic function. At present, no effective acute treatment or rehabilitative therapy exists. Recently, several studies show that Riluzole has neuroprotective effect and promotes functional and neurological recoveries in animal models of brain and spinal cord ischemic and traumatic injuries; however, hepatotoxicity is a significant side effect concern for this therapy. Therefore, pharmacokinetic (PK) and pharmacodynamic (PD) study of Riluzole is of great importance for us to understand its toxicity and efficacy in acute SCI patients. We hypothesize that spinal cord injury and formulation/administration alteration would affect the pharmacokinetics of Riluzole, and PK/PD studies would enable us to establish the correlation of Riluzole concentration/exposure with its toxicity and efficacy outcomes. Our project has three specific aims: 1) To investigate whether the change of formulation/administration would alter the PK of Riluzole. The rat model was used and different formulations of Riluzole were administrated (oral: crushed tablet, crushed paste, crushed paste with glycerin, suspension and solution; i.v.: solution). The PK of Riluzole in different treatment groups would be characterized and compared. 2) To explore the impact of SCI on Riluzole PK. Spinal cord injured and non-injured control rats were used to establish the impacts of acute SCI on Riluzole PK by monitoring PK profiles of Riluzole in plasma, brain and spinal cord after single and multiple doses. 3) To characterize individual and population PK of Riluzole and establish PK/PD correlation of Riluzole in terms of concentration/exposure with its toxicity and efficacy in acute SCI patients. Thirty-five individuals with acute SCI, American Spinal Injury Association (ASIA) Impairment Scale (AIS) 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 Trial Network (NACTN) for the treatment of SCI, received 50 mg Riluzole twice daily for 28 doses. The first dose was administered at a mean of 8.7 ± 2.2 hours post-injury. Trough plasma samples were collected within 1 hour pre-dose, and peak plasma samples were collected 2 hours post-dose on Day 3 and 14 of treatment. The data were analyzed for individual and population PK using basic structural and covariate models. The PK measures studied were the peak concentration (Cmax), trough concentration (Cmin), systemic exposure (AUC0-12), clearance (CL/F), and volume of distribution (V/F) normalized by the bioavailability (F). Linear and logistic regressions were used to establish the PK/PD correlations of Riluzole in acute SCI patients. Riluzole concentrations were quantified by a validated high-performance liquid chromatographic with UV detection assay. In animal models, the alteration of formulation from crushed tablet to liquid increased the bioavailability of Riluzole, but did not affect its intrinsic PK characteristics; Acute SCI resulted in higher plasma, brain and spinal cord concentrations in acute phase of SCI after multiple I.P. doses, which was due to a slower elimination caused by an impaired hepatic clearance. In acute SCI patients, the Cmax and AUC0-12 of Riluzole were lower than those in ALS patients on the same dose basis, due to a higher CL and a larger V. The PK of Riluzole (Cmax, Cmin, AUC0-12, CL/F, and V/F) changed during the acute and subacute phases of SCI in the 14 days of therapy. It was consistently observed in patients at all clinical sites that Cmax, Cmin, and AUC0-12 (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 a lower CL (49.5 vs 106.2 L/hour) and a smaller V (557.1 vs 1297.9 L) on Day 3. Neither fluid imbalance nor cytochrome P 1A2 induction due to concomitant medications was identified during the treatment course to account for such increases in V and CL on Day 14, respectively. Possible mechanisms underlying these changes are discussed. The changes of motor and sensory scores at 3-month follow-up had good correlation with Day 3 AUC/kg. The establishments of PK-PD correlation could be used to predict the PD outcomes in the future clinical trial.
dc.description.departmentPharmacological and Pharmaceutical Sciences, Department of
dc.format.digitalOriginborn digital
dc.rightsThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).
dc.subjectSpinal cord injuries
dc.subjectPK/PD Correlation
dc.titleImpacts of Spinal Cord Injury and Formulation on Riluzole Pharmacokinetics and Pharmacokinetics/Pharmacodynamics (PK/PD) Correlation
dc.type.genreThesis of Pharmacy and Pharmaceutical Sciences, Department of and Pharmaceutical Sciences of Houston


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