{"id":{"repo_id":"houston","oai_identifier":"oai:uh-ir.tdl.org:10657/19590"},"canonical_url":"https://search.dev.ndltd.org/etd/houston/oai:uh-ir.tdl.org:10657/19590","repository":{"repo_id":"houston","name":"University of Houston","base_url":"https://uh-ir.tdl.org/server/oai/request"},"display":{"title":"Model-Informed Drug Development of Riluzole for Neuroprotection in Acute Spinal Cord Injury: Integrating Pharmacokinetics, Pharmacodynamics, and Clinical Outcomes for Precision Medicine","abstract":"Traumatic spinal cord injury (SCI) is a debilitating condition with no FDA-approved pharmacological therapies. Progress in therapeutic development has been hindered by the complexity of SCI pathophysiology, considerable interindividual variability, and a relatively small patient population. Riluzole, a sodium channel blocker with established neuroprotective properties, was evaluated in the Riluzole in Spinal Cord Injury Study (RISCIS), a Phase II/III clinical trial conducted by the North American Clinical Trials Network (NACTN). This research represents the pharmacokinetic (PK) sub-study of RISCIS and investigates the therapeutic potential of riluzole to improve neurological outcomes using an integrated, model-informed framework that incorporates pharmacokinetics, pharmacodynamics (PD), and clinical outcomes (CO). By leveraging modeling and simulation, this approach provides a strategy to address clinical heterogeneity and guide individualized treatment based on drug exposure, biomarker response, and recovery profiles. The first objective involved exploring clinical responses to riluzole through comprehensive exploratory data analysis using the RISCIS PK sub-study dataset. Results indicated that individuals with incomplete cervical SCI, particularly those classified as American Spinal Injury Association Impairment Scale (AIS) C, experienced greater improvement in upper extremity motor function in the C7–T1 segments when treated with riluzole compared to placebo. Additionally, a reduction in pain scores on Day 14 suggested a potential short-term symptomatic benefit associated with riluzole treatment. The second objective focused on characterizing riluzole disposition over the 14-day dosing period through development of a time-varying one-compartment PK model, which revealed increasing clearance and volume of distribution over the time period of 2-week treatment. PK/PD models incorporating delayed drug effects and disease progression dynamics were then used to evaluate relationships of alanine aminotransferase (ALT), a marker of hepatic safety, with riluzole exposure and phosphorylated neurofilament heavy chain (pNFH), a biomarker of axonal injury. These models captured subtle exposure-related effects not evident through conventional group-level analyses, demonstrating the added value of model-based methods in uncovering interindividual variability in both efficacy and safety parameters. The third objective aimed to characterize exposure–response relationships by applying response surface methodology (RSM) to integrate PK, PD, and clinical outcome data. RSM models revealed non-linear interactions between riluzole AUC, early clinical or biomarker predictors, and six-month motor recovery. Mid-range AUC values were associated with the most favorable outcomes, suggesting the existence of an optimal therapeutic window. Among candidate predictors, Day 7 AUC emerged as the earliest reliable indicator of long-term benefit, while Day 14 motor scores provided a stable reference for recovery assessment. Based on these findings, PK simulations were conducted to evaluate individualized dosing strategies that maintain exposure within the identified target range, accounting for time-varying PK behavior and patient-specific variability. This modeling and simulation framework supports the feasibility of precision dosing in SCI and offers a path forward for tailoring interventions to individual recovery trajectories. Despite limitations related to sample size and variability, this study demonstrates the utility of an integrated PK/PD/CO modeling approach to inform exposure-guided therapy in acute SCI. The findings establish a foundation for future research to aim at optimizing riluzole dosing, incorporating biomarkers into trial design, and advancing personalized neuroprotective strategies.","abstract_html":"Traumatic spinal cord injury (SCI) is a debilitating condition with no FDA-approved pharmacological therapies. Progress in therapeutic development has been hindered by the complexity of SCI pathophysiology, considerable interindividual variability, and a relatively small patient population. Riluzole, a sodium channel blocker with established neuroprotective properties, was evaluated in the Riluzole in Spinal Cord Injury Study (RISCIS), a Phase II/III clinical trial conducted by the North American Clinical Trials Network (NACTN). This research represents the pharmacokinetic (PK) sub-study of RISCIS and investigates the therapeutic potential of riluzole to improve neurological outcomes using an integrated, model-informed framework that incorporates pharmacokinetics, pharmacodynamics (PD), and clinical outcomes (CO). By leveraging modeling and simulation, this approach provides a strategy to address clinical heterogeneity and guide individualized treatment based on drug exposure, biomarker response, and recovery profiles. The first objective involved exploring clinical responses to riluzole through comprehensive exploratory data analysis using the RISCIS PK sub-study dataset. Results indicated that individuals with incomplete cervical SCI, particularly those classified as American Spinal Injury Association Impairment Scale (AIS) C, experienced greater improvement in upper extremity motor function in the C7–T1 segments when treated with riluzole compared to placebo. Additionally, a reduction in pain scores on Day 14 suggested a potential short-term symptomatic benefit associated with riluzole treatment. The second objective focused on characterizing riluzole disposition over the 14-day dosing period through development of a time-varying one-compartment PK model, which revealed increasing clearance and volume of distribution over the time period of 2-week treatment. PK/PD models incorporating delayed drug effects and disease progression dynamics were then used to evaluate relationships of alanine aminotransferase (ALT), a marker of hepatic safety, with riluzole exposure and phosphorylated neurofilament heavy chain (pNFH), a biomarker of axonal injury. These models captured subtle exposure-related effects not evident through conventional group-level analyses, demonstrating the added value of model-based methods in uncovering interindividual variability in both efficacy and safety parameters. The third objective aimed to characterize exposure–response relationships by applying response surface methodology (RSM) to integrate PK, PD, and clinical outcome data. RSM models revealed non-linear interactions between riluzole AUC, early clinical or biomarker predictors, and six-month motor recovery. Mid-range AUC values were associated with the most favorable outcomes, suggesting the existence of an optimal therapeutic window. Among candidate predictors, Day 7 AUC emerged as the earliest reliable indicator of long-term benefit, while Day 14 motor scores provided a stable reference for recovery assessment. Based on these findings, PK simulations were conducted to evaluate individualized dosing strategies that maintain exposure within the identified target range, accounting for time-varying PK behavior and patient-specific variability. This modeling and simulation framework supports the feasibility of precision dosing in SCI and offers a path forward for tailoring interventions to individual recovery trajectories. Despite limitations related to sample size and variability, this study demonstrates the utility of an integrated PK/PD/CO modeling approach to inform exposure-guided therapy in acute SCI. The findings establish a foundation for future research to aim at optimizing riluzole dosing, incorporating biomarkers into trial design, and advancing personalized neuroprotective strategies.","abstract_has_math":false,"creators":["Park, Junghwa"],"institution":"University of Houston","degree_name":"Doctor of Philosophy","degree_level":null,"degree_discipline":"Pharmaceutics","degree_department":null,"school":null,"contributors":[],"advisors":["Chow, Diana S-L.","Guest, James D."],"committee_chairs":[],"committee_members":["Cuny, Gregory D.","Wang, Yow-Ming","Trivedi, Meghana"],"year":2025,"date_issued":"2025-05","date_published":"2025-05","updated_at":"2026-07-24T02:32:58Z","subjects":["Pharmacology"],"languages":["English"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/10657/19590","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Chow, Diana S-L.","Guest, James D."]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Cuny, Gregory D.","Wang, Yow-Ming","Trivedi, Meghana"]},{"key":"dc:creator","label":"Author","values":["Park, Junghwa"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-06-25T05:02:42Z"]},{"key":"dc:date.issued","label":"Date","values":["2025-05"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Pharmaceutics"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Houston"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Pharmacology"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["English"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/10657/19590"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Traumatic spinal cord injury (SCI) is a debilitating condition with no FDA-approved pharmacological therapies. Progress in therapeutic development has been hindered by the complexity of SCI pathophysiology, considerable interindividual variability, and a relatively small patient population. Riluzole, a sodium channel blocker with established neuroprotective properties, was evaluated in the Riluzole in Spinal Cord Injury Study (RISCIS), a Phase II/III clinical trial conducted by the North American Clinical Trials Network (NACTN). This research represents the pharmacokinetic (PK) sub-study of RISCIS and investigates the therapeutic potential of riluzole to improve neurological outcomes using an integrated, model-informed framework that incorporates pharmacokinetics, pharmacodynamics (PD), and clinical outcomes (CO). By leveraging modeling and simulation, this approach provides a strategy to address clinical heterogeneity and guide individualized treatment based on drug exposure, biomarker response, and recovery profiles. The first objective involved exploring clinical responses to riluzole through comprehensive exploratory data analysis using the RISCIS PK sub-study dataset. Results indicated that individuals with incomplete cervical SCI, particularly those classified as American Spinal Injury Association Impairment Scale (AIS) C, experienced greater improvement in upper extremity motor function in the C7–T1 segments when treated with riluzole compared to placebo. Additionally, a reduction in pain scores on Day 14 suggested a potential short-term symptomatic benefit associated with riluzole treatment. The second objective focused on characterizing riluzole disposition over the 14-day dosing period through development of a time-varying one-compartment PK model, which revealed increasing clearance and volume of distribution over the time period of 2-week treatment. PK/PD models incorporating delayed drug effects and disease progression dynamics were then used to evaluate relationships of alanine aminotransferase (ALT), a marker of hepatic safety, with riluzole exposure and phosphorylated neurofilament heavy chain (pNFH), a biomarker of axonal injury. These models captured subtle exposure-related effects not evident through conventional group-level analyses, demonstrating the added value of model-based methods in uncovering interindividual variability in both efficacy and safety parameters. The third objective aimed to characterize exposure–response relationships by applying response surface methodology (RSM) to integrate PK, PD, and clinical outcome data. RSM models revealed non-linear interactions between riluzole AUC, early clinical or biomarker predictors, and six-month motor recovery. Mid-range AUC values were associated with the most favorable outcomes, suggesting the existence of an optimal therapeutic window. Among candidate predictors, Day 7 AUC emerged as the earliest reliable indicator of long-term benefit, while Day 14 motor scores provided a stable reference for recovery assessment. Based on these findings, PK simulations were conducted to evaluate individualized dosing strategies that maintain exposure within the identified target range, accounting for time-varying PK behavior and patient-specific variability. This modeling and simulation framework supports the feasibility of precision dosing in SCI and offers a path forward for tailoring interventions to individual recovery trajectories. Despite limitations related to sample size and variability, this study demonstrates the utility of an integrated PK/PD/CO modeling approach to inform exposure-guided therapy in acute SCI. The findings establish a foundation for future research to aim at optimizing riluzole dosing, incorporating biomarkers into trial design, and advancing personalized neuroprotective strategies."]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Model-Informed Drug Development of Riluzole for Neuroprotection in Acute Spinal Cord Injury: Integrating Pharmacokinetics, Pharmacodynamics, and Clinical Outcomes for Precision Medicine"]}]}],"canonical_facts":{"dc:contributor.advisor":["Chow, Diana S-L.","Guest, James D."],"dc:contributor.committeemember":["Cuny, Gregory D.","Wang, Yow-Ming","Trivedi, Meghana"],"dc:creator":["Park, Junghwa"],"dc:date.accessioned":["2025-06-25T05:02:42Z"],"dc:date.issued":["2025-05"],"dc:description.abstract":["Traumatic spinal cord injury (SCI) is a debilitating condition with no FDA-approved pharmacological therapies. Progress in therapeutic development has been hindered by the complexity of SCI pathophysiology, considerable interindividual variability, and a relatively small patient population. Riluzole, a sodium channel blocker with established neuroprotective properties, was evaluated in the Riluzole in Spinal Cord Injury Study (RISCIS), a Phase II/III clinical trial conducted by the North American Clinical Trials Network (NACTN). This research represents the pharmacokinetic (PK) sub-study of RISCIS and investigates the therapeutic potential of riluzole to improve neurological outcomes using an integrated, model-informed framework that incorporates pharmacokinetics, pharmacodynamics (PD), and clinical outcomes (CO). By leveraging modeling and simulation, this approach provides a strategy to address clinical heterogeneity and guide individualized treatment based on drug exposure, biomarker response, and recovery profiles. The first objective involved exploring clinical responses to riluzole through comprehensive exploratory data analysis using the RISCIS PK sub-study dataset. Results indicated that individuals with incomplete cervical SCI, particularly those classified as American Spinal Injury Association Impairment Scale (AIS) C, experienced greater improvement in upper extremity motor function in the C7–T1 segments when treated with riluzole compared to placebo. Additionally, a reduction in pain scores on Day 14 suggested a potential short-term symptomatic benefit associated with riluzole treatment. The second objective focused on characterizing riluzole disposition over the 14-day dosing period through development of a time-varying one-compartment PK model, which revealed increasing clearance and volume of distribution over the time period of 2-week treatment. PK/PD models incorporating delayed drug effects and disease progression dynamics were then used to evaluate relationships of alanine aminotransferase (ALT), a marker of hepatic safety, with riluzole exposure and phosphorylated neurofilament heavy chain (pNFH), a biomarker of axonal injury. These models captured subtle exposure-related effects not evident through conventional group-level analyses, demonstrating the added value of model-based methods in uncovering interindividual variability in both efficacy and safety parameters. The third objective aimed to characterize exposure–response relationships by applying response surface methodology (RSM) to integrate PK, PD, and clinical outcome data. RSM models revealed non-linear interactions between riluzole AUC, early clinical or biomarker predictors, and six-month motor recovery. Mid-range AUC values were associated with the most favorable outcomes, suggesting the existence of an optimal therapeutic window. Among candidate predictors, Day 7 AUC emerged as the earliest reliable indicator of long-term benefit, while Day 14 motor scores provided a stable reference for recovery assessment. Based on these findings, PK simulations were conducted to evaluate individualized dosing strategies that maintain exposure within the identified target range, accounting for time-varying PK behavior and patient-specific variability. This modeling and simulation framework supports the feasibility of precision dosing in SCI and offers a path forward for tailoring interventions to individual recovery trajectories. Despite limitations related to sample size and variability, this study demonstrates the utility of an integrated PK/PD/CO modeling approach to inform exposure-guided therapy in acute SCI. The findings establish a foundation for future research to aim at optimizing riluzole dosing, incorporating biomarkers into trial design, and advancing personalized neuroprotective strategies."],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://hdl.handle.net/10657/19590"],"dc:language.iso":["English"],"dc:subject":["Pharmacology"],"dc:title":["Model-Informed Drug Development of Riluzole for Neuroprotection in Acute Spinal Cord Injury: Integrating Pharmacokinetics, Pharmacodynamics, and Clinical Outcomes for Precision Medicine"],"dc:type":["Thesis"],"thesis:degree_discipline":["Pharmaceutics"],"thesis:degree_name":["Doctor of Philosophy"],"thesis:institution_name":["University of Houston"]},"updated_at":"2026-07-24T02:32:58Z"}