Pharmacokinetics and Pharmacodynamics of Riluzole in Acute Spinal Cord Injury Patients

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dc.contributor.advisorChow, Diana Shu-Lian
dc.contributor.committeeMemberLiu, Xinli
dc.contributor.committeeMemberCuny, Gregory D.
dc.contributor.committeeMemberGrossman, Robert G.
dc.contributor.committeeMemberRytting, Erik
dc.creatorNguyen, Ashley
dc.date.accessioned2022-06-30T22:34:22Z
dc.date.createdMay 2021
dc.date.issued2021-05
dc.date.submittedMay 2021
dc.date.updated2022-06-30T22:34:23Z
dc.description.abstractRiluzole, a benzothiazole sodium channel blocker that received FDA approval to attenuate neurodegeneration in amyotrophic lateral sclerosis (ALS) 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. In this project, we studied the time-variant pharmacokinetics of a potential neuroprotective therapy, riluzole, and its pharmacodynamic effects on an axonal injury biomarker, pNF-H and motor functions. We aimed to: (1) Characterize the longitudinal impacts of SCI on the pharmacokinetics (PK) of riluzole. A one-compartment with first-order elimination population PK model for riluzole incorporating time-dependent clearance and volume of distribution was developed from combined data of the Phase I and the ongoing Phase II/III trials. With the developed model, a rational, optimal dosing scheme can be designed with time-dependent modification that preserves the required therapeutic exposure of riluzole; (2) Investigate the pharmacodynamic (PD) of riluzole and establish the relationship between riluzole PK and neurological outcomes and adverse effects of the treatment. In this aim, the time-course of PD measurements of efficacy, such as the change in motor/ sensory scores of International Standard for Neurological Classification of Spinal Cord Injury (ISNCSCI) and the axonal damage biomarker, phosphorylated neurofilament heavy chain (pNF-H), were performed. Assessment of liver toxicity using toxicodynamic (TD) measurements, such as aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase were also executed. A meaningful correlation was established between the improvement in motor score at 6-month with treatment exposure and baseline total motor scores. Patients with baseline score of 10 and above benefited from the optimal exposure range of 12 – 33 mg*h/ml. The PD models of pNF-H revealed the riluzole efficacy as treated subjects exhibited a diminished increase in natural progression of pNF-H, indicative of reduced axonal breakdown. A mechanistic PKPD model was developed to describe the time course of pNF-H in relation to exposure of riluzole that can be used for simulation purposes. Assessment of liver toxicity markers also showed that there was no apparent toxicity related to the current riluzole treatment; (3) Study the effects of SCI and riluzole therapy on concomitant medications. SCI patients take up to 21 concomitant medications, of which, oxycodone and acetaminophen were identified as the most common among patients. Since riluzole is a substrate of P-glycoprotein (P-gp), concurrent administration with another P-gp substrate such as oxycodone will alter riluzole PK and vice versa. A sensitive and robust LC-MS/MS assay capable of simultaneous quantification of oxycodone and acetaminophen was developed and validated to determine all patients’ concentrations of both drugs, enabling the drug-drug interaction investigation. Acetaminophen concentrations showed no significant difference between riluzole treated and placebo groups. However, oxycodone exposure was lower in riluzole treated group compared to placebo group. It is speculated that riluzole may attenuate oxycodone efflux by P-gp at the blood-brain-spinal cord barriers via competition for transport, thus enhance interactions of oxycodone with opioid receptors. To our knowledge, the effects of riluzole treatment on pain management therapy has not been fully characterized. This study will add valuable information in designing optimal dosage regimen for therapeutics used in SCI management. To date, no drug therapy has shown significant efficacy in improving functional outcomes in patients with SCI. The development of effective treatment for SCI is challenging due to the substantial initial mechanical damage and subsequent biochemical destructive cascade. Understanding the PK and PD of therapeutics, as well as how the disease progression that can affect these properties, can facilitate the future drug development via optimal dosing regimen design.
dc.description.departmentPharmacological and Pharmaceutical Sciences, Department of
dc.format.digitalOriginborn digital
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/10657/10236
dc.language.isoeng
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.subjectclinical trial
dc.subjectpharmacokinetics
dc.subjectpharmacodynamics
dc.subjectclinical outcomes
dc.subjectpharmacometrics
dc.subjectmathematical modeling
dc.titlePharmacokinetics and Pharmacodynamics of Riluzole in Acute Spinal Cord Injury Patients
dc.type.dcmiText
dc.type.genreThesis
local.embargo.lift2023-05-01
local.embargo.terms2023-05-01
thesis.degree.collegeCollege of Pharmacy
thesis.degree.departmentPharmacological and Pharmaceutical Sciences, Department of
thesis.degree.disciplinePharmaceutics
thesis.degree.grantorUniversity of Houston
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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