Population Pharmacokinetics of Sodium Selenate: A Potential Disease Modifying Therapy for Chronic Drug-resistant Temporal Lobe Epilepsy
Abstract number :
2.367
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2024
Submission ID :
1083
Source :
www.aesnet.org
Presentation date :
12/8/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Chenxu Li, MS – University of Minnesota
Lucy Vivash, PhD – Monash University
Cassandra Marotta, BS – Monash University
Usha Mishra, MS – University of Minnesota
Dennis Velakoulis, MBBS – Royal Melbourne Hospital, The University of Melbourne
Chris Hovens, PhD – The University of Melbourne
Terence J O'Brien, MBBS MD – School of Translational Medicine, Monash University, The Alfred Centre
Lisa Coles, PhD – University of Minnesota
Rationale: Current antiseizure medications are considered symptomatic treatments that do not target epileptogenesis or alleviate disease severity or neuropsychiatric comorbidities in established epilepsy. Drug-resistant epilepsy is associated with significant morbidity, with fewer than 5% of patients eligible for resective epilepsy surgery, the only established disease-modifying treatment. Thus, developing non-surgical therapies with sustained disease-modifying effects for drug-resistant epilepsy would be a substantial advancement. Preclinical evidence suggests that sodium selenate exhibits antiepileptogenic and disease modifying potential by specifically reducing hyperphosphorylated tau (Casillas-Espinosa et al., 2023 PMID: 36892461). Previous clinical studies have verified its safety and tolerability with chronic treatment in a range of neurodegenerative diseases. We are currently conducting a phase II multicenter, double-blind clinical trial investigating the antiseizure and disease-modifying effects of sodium selenate in patients with drug-resistant temporal lobe epilepsy (Vivash et al., 2023 PMID: 37890967). The objective of the study reported here is to develop a population pharmacokinetic (PK) model of sodium selenate to inform dosage regimens for treating epilepsy and other neurodegenerative diseases, including traumatic brain injury, and guide the design of future clinical trials.
Methods: The population PK analysis was performed using data from a Phase Ib open-label study of sodium selenate in patients with behavioral variant frontotemporal dementia. Participants were administered either 10 mg or 15 mg doses of sodium selenate three times daily for a total duration of 52 weeks (Vivash et al., 2022 PMID: 35574563). Plasma concentrations of sodium selenate were measured at various time points and utilized in the development of the population PK model. The PK model was constructed using the Phoenix nonlinear mixed-effects modeling approach.
Results: The PK of sodium selenate were well described using a two-compartment model with first-order oral absorption. Residual unexplained variability was modeled using a proportional error model. The parameter estimates (%CV) of absorption rate constant (Ka), clearance (CL/F), intercompartmental clearance (CL2/F), central volume of distribution (V/F), peripheral volume of distribution (V2/F) were 8.35 h-1 (15%), 9.53 mL/h (18%), 14.72 mL/h (50%), 0.003 mL (8%), and 49.56 mL (29%), respectively. The estimated between-subject variability of CL was 15%, and the unexplained residual variability was 20%. The model was robust and adequate based on the goodness of fit plots.
Conclusions: This is the first population PK model of sodium selenate developed in patients. Our model offers significant insights into the PK properties of sodium selenate and will be instrumental in guiding future clinical studies on drug-resistant epilepsy and other neurodegenerative diseases.
Funding: This study was funded by a philanthropic donation to the RMH Neuroscience Foundation and an Australian Government Medical Research Future Fund grant.
Anti-seizure Medications