Dose Optimization Using Population PK for an Orphan Drug
RAPALIMUS® Tablets (sirolimus) is Nobelpharma’s orphan drug developed from an oral medication that is sold as an organ transplant immunosuppressant by Pfizer Inc. in the US. Due to its properties as an mTOR inhibitor, physicians in academia and researchers had been actively studying and collecting data in an effort to find applications of RAPALIMUS for other diseases. Based on the findings of this research, Japan-based Nobelpharma obtained marketing approval from the Pharmaceuticals and Medical Devices Agency (PMDA), Japan’s health authority, for RAPALIMUS as the first medication for lymphangioleiomyomatosis, a lung disease caused by abnormal growth of smooth muscle cells, in 2014.
Recently, Nobelpharma gained approval for a new indication for RAPALIMUS to treat a refractory lymphatic disease by using data from investigator-driven clinical trials led by Michio OZEKI M.D. (Department of Pediatrics, Gifu University, Japan). These trials targeted intractable lymphatic anomalies that mainly affect children (Lymphatic malformation, Generalized lymphatic anomaly, Gorham-Stout disease, and Lymphangiectasia). This project was supported by a Certara consulting team that established a population pharmacokinetic model, ran simulations for dose-setting based on body surface area, and prepared relevant document for approval, among other vital tasks.
In 2019, Nobelpharma worked alongside Michio OZEKI M.D. and collaborated with Certara to determine the optimum dose of RAPALIMUS by performing a population pharmacokinetic (PPK) analysis with a non-linear mixed-effects model. This analysis was performed using RAPALIMUS trough levels in whole blood acquired from clinical trials of patients with intractable lymphatic anomalies, clinical research involving patients with intractable vascular tumors and vascular malformations, clinical research involving patients with intractable lymphatic anomalies, clinical studies of healthy adults, and clinical studies of patients with lymphangioleiomyomatosis.
As a result of this analysis, factors affecting the pharmacokinetics of RAPALIMUS were identified and drug exposure levels were described based on a two-compartment model with a first-order absorption process that incorporated adjustments for body weight and age in accordance with the principles of allometry. This information was also included in the drug package insert. Due to large individual differences in pharmacokinetics, post-marketing therapeutic drug monitoring (TDM) of individual patients receiving doses in both body surface area categories was also considered important, and a recommendation to “adjust the dose depending on patient status and trough levels in the blood” was included in the drug label.
Given that the clinical trials targeted rare diseases and were conducted in high-risk patients, dose-optimization was challenging due to the small number of patients.
About Nobelpharma Co., Ltd.
Nobelpharma Co., Ltd. was founded in 2003 with a mission to “Contribute to Society by Providing Critical Pharmaceuticals and Medical Devices for neglected diseases.” Nobelpharma endeavors to accelerate drug development by developing pharmaceuticals and medical devices that meet medical needs not addressed by other companies and quickly deliver therapeutic drugs to the patients who await them.
