Development of an IV Topiramate Population PK Model Utilizing Data from Healthy Participants and Patients
Abstract number :
3.402
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2024
Submission ID :
620
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Adeboye Bamgboye, PhD student – University of Minnesota
James Cloyd, PharmD – University of Minnesota
Bernard King, MD,MBA – CURx Pharmaceuticals
Annie Clark, PhD – Pliant Therapeutics
Susan Marino, PhD – University of Minnesota
James White, MD – Minnesota Epilepsy Group
Ilo Leppik, MD – University of Minnsota Medical Center
Robert Kriel, MD – University of Minnesota
Lisa Coles, PhD – University of Minnesota
Rationale: Topiramate (TPM) is an antiseizure medication indicated for several epilepsy syndromes and migraine prophylaxis. However, the only available TPM products are oral formulations, which poses a challenge for patients who cannot take TPM by mouth. This can lead to an interruption of therapy with potentially undesirable consequences. CURx Pharmaceuticals is developing an intravenous TPM (IV TPM) formulation that would permit continuity of therapy when oral administration is not feasible. To optimize the use of the IV formulation, a comprehensive understanding of its pharmacokinetics is crucial. We analyzed data from three IV TPM studies to investigate the effect of enzyme-inducing comedications on TPM pharmacokinetics.
Methods: IV TPM plasma concentrations obtained from two previously published clinical studies (12 healthy participants and 20 patients with either migraine or epilepsy taking TPM) and Phase I data from CURx (25 healthy participants) were used for modeling. The individuals in the first two studies received stable-labeled IV TPM (25-100mg doses over 10-15 minutes). Eight of the patients with epilepsy were taking enzyme-inducing medications. The individuals in the Phase I study received IV TPM in 50 or 100-mg doses over 30 minutes. A population pharmacokinetic model was developed using Certara Phoenix NLME (Phoenix v 8.4). Covariate evaluation included enzyme-inducing comedications, baseline weight, sex, and disease status (healthy or patient).
Results: A two-compartment pharmacokinetic model with linear elimination best described IV TPM disposition. The clearance (CL) and volume of distribution (Vd) parameters were allometrically scaled using an exponent of 0.75 for CL and 1.0 for Vd. The typical values (% relative standard error [RSE}) for central and peripheral volumes were 0.33L/Kg (11.1) and 0.58L/Kg (3.7), respectively. The typical values (%RSE) for central and intercompartmental CLs were 0.02L/hr/kg (2.9) and 0.34L/hr/kg (31.9). Covariate analysis revealed that only comedications had an effect on central CL (p< 0.01), which was doubled for patients on enzyme-inducing comedications (increasing from 0.02L/hr/kg to 0.04L/hr/kg). Although enzyme-inducing comedications increase
Anti-seizure Medications