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.
The patient group was small and contained a limited variety of patient characteristics, hence dosage standardization (for inclusion in the drug package insert) would have been impossible without the PPK model-based simulation technique. We worked with Certara to resolve this problem.
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.