Population pharmacokinetics of everolimus in patients with seizures associated with focal cortical dysplasia

Jinha Park; Se Hee Kim; Jongsung Hahn; Hoon-Chul Kang; Sang-Guk Lee; Heung Dong Kim; Min Jung Chang

doi:10.3389/fphar.2023.1197549

Population pharmacokinetics of everolimus in patients with seizures associated with focal cortical dysplasia

Front Pharmacol. 2023 Nov 24:14:1197549. doi: 10.3389/fphar.2023.1197549. eCollection 2023.

Authors

Jinha Park^#^{1

2}, Se Hee Kim^#³, Jongsung Hahn⁴, Hoon-Chul Kang³, Sang-Guk Lee⁵, Heung Dong Kim^#^{3

6}, Min Jung Chang^#^{1

2

7}

Affiliations

¹ Department of Pharmaceutical Medicine and Regulatory Science, Colleges of Medicine and Pharmacy, Yonsei University, Seoul, Republic of Korea.
² Department of Pharmacy, College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Seoul, Republic of Korea.
³ Pediatric Neurology, Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Epilepsy Research Institute, Seoul, Republic of Korea.
⁴ Department of Pharmacy, Jeonbuk National University, Jeonju, Republic of Korea.
⁵ Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
⁶ Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, Republic of Korea.
⁷ Graduate Program of Industrial Pharmaceutical Science, Yonsei University, Incheon, Republic of Korea.

^# Contributed equally.

Abstract

Background: Everolimus is an inhibitor of mammalian target of rapamycin complex 1. As mutations in TSC1 and TSC2, which cause partial-onset seizures associated with TSC, were found in focal cortical dysplasia type Ⅱ (FCD Ⅱ) patients, a clinical trial has been performed to explore the efficacy and safety of everolimus in FCD patients. However, no dosage regimen was determined to treat FCD II. To recommend an optimal dose regimen for FCD patients, a population pharmacokinetic model of everolimus in FCD patients was developed. Methods: The data of everolimus were collected from September 2017 to May 2020 in a tertiary-level hospital in Korea. The model was developed using NONMEM^® software version 7.4.1 (Icon Development Solutions, Ellicott City, MD, United States). Results: The population pharmacokinetics of everolimus was described as the one-compartment model with first-order absorption, with the effect of BSA on clearance. The final model was built as follows: TVCL = 12.5 + 9.71 × (BSA/1.5), TVV = 293, and TVKA = 0.585. As a result of simulation, a dose higher than 7 mg/m² is needed in patients with BSA 0.5 m², and a dose higher than 6 mg/m² is needed in patients with BSA 0.7 m². A dose of 4.5 mg/m² is enough in the population with BSA higher than 1.5 m² to meet the target trough range of 5-15 ng/mL. Conclusion: Based on the developed pharmacokinetics model, the optimal dose of everolimus in practice was recommended by considering the available strengths of Afinitor disperz^®, 2 mg, 3 mg, and 5 mg.

Keywords: epilepsy; everolimus; focal cortical dysplasia; non-linear mixed-effect modeling; population pharmacokinetics.

Grants and funding

This study analyzed data that were obtained during “A Study Investigating the Anti-epileptic Efficacy of Afinitor (Everolimus) in Patients with Refractory Seizures Who Have Focal Cortical Dysplasia Type II (FCD II) (NCT03198949)” funded by Novartis. This work was supported by a grant (No. 2023R1A2C1004568) from the National Research Foundation (NRF) of Korea, funded by the Korean government (Ministry of Science, ICT & Future Planning).