Alternate Dosing Regimens for an Immediate Release Formulation of the Novel Antiseizure Medication LP352 Based on Pharmacokinetics (Plasma and CSF) and Pharmacodynamics (QEEG)
Abstract number :
3.269
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2023
Submission ID :
1074
Source :
www.aesnet.org
Presentation date :
12/4/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Randall Kaye, MD – Longboard Pharmaceuticals, Inc.
Nuggehally Srinivas, PhD – Longboard Pharmaceuticals, Inc.; Dewey McLin, PhD – Longboard Pharmaceuticals, Inc.; Chad Orevillo, MPH – Longboard Pharmaceuticals, Inc.; David Vossler, MD – University of Washington, Seattle; Rosa Chan, PhD – Longboard Pharmaceuticals, Inc.
Rationale: LP352 is a potent and highly selective 5-HT2C superagonist in development for the treatment of developmental and epileptic encephalopathies (DEE). LP352 elicits a greater response at the 5-HT2C receptor than the endogenous ligand serotonin and has no detected activity at other 5-HT2 receptors associated with significant adverse effects: 5-HT2B (valvular heart disease and pulmonary arterial hypertension) and 5-HT2A (insomnia, hallucinations, and euphoria). Relative to TID dosing, BID dosing in patients with DEE may lower the therapeutic burden by increasing patient adherence to treatment and easing delivery of treatment for caregivers. Therefore, we evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of TID and BID doses of LP352. Such data allows comparison of TID versus BID dosing and enables feasibility assessment of BID dosing in future clinical studies.
Methods: The PK (assessed in plasma and cerebrospinal fluid [CSF]) and PD (assessed by quantitative electroencephalogram [QEEG] activity) of multiple oral BID doses of LP352 were evaluated in three cohorts of healthy adults (18-55 yr, n=20). Following an initial two to four days of up titration (depending on target dose), subjects were dosed for six to eight days at the target doses of 12 mg, 15 mg, or 18 mg BID. Serial plasma samples were obtained after a single dose and after multiple doses on days eight, nine, and ten. Serial CSF samples were obtained at steady state (day 11). Serial QEEGs with eyes in open and closed positions were recorded at baseline and days -1, 1, 3 or 5, 10, and day 16 (at trough). LP352 concentrations were quantified in various clinical samples using validated bioanalytical methods. Standard PK parameters were calculated. All QEEG assessments used state-of-the-art recording instruments and were performed by qualified EEG technologists.
Results: Across BID dose ranges, the observed PK in both plasma and CSF was dose linear. There was a strong correlation of plasma and CSF PK parameters, including Cmax and AUCtau. The CSF/plasma exposure ratio for AUCtau was generally >0.84 at the 3 BID doses. Average plasma concentrations over the dosing interval were comparable (~28%) between the 18 mg BID and 12 mg TID groups. In the CSF, LP352 concentrations generally exceeded the Ki value (~14 ng/mL) for 5-HT2C agonism by ~2-fold in both the 18 mg BID and 12 mg TID dosing groups. Furthermore, as observed previously for TID dosing, the QEEG data across multiple spectral bands for BID dosing of LP352 was consistent with successful receptor engagement in the brain. The BID dosing of LP352 showed mild to moderate treatment-emergent adverse events (AEs) that were consistent with earlier TID studies; there were no severe AEs.
Conclusions: The plasma and CSF PK data of LP352, in conjunction with the observed PD QEEG changes, demonstrate that BID dosing of LP352 is a viable alternative option for use in future clinical studies.
Funding: This study was sponsored by Longboard Pharmaceuticals, Inc.
Anti-seizure Medications