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.
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.
Certara’s lead consultant, Dr. Mayumi Hasegawa, quickly understood our requests, performed her assessments, and communicated her recommendations to other analysts clearly and concisely, which was of immense help. We are also grateful to Mayumi for resolving many of our concerns.
Going forward, we want to collect data that allows for more robust simulations and intend to update the PPK model. We would also like to develop this model into a PK/PD model for other diseases."
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