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 CS Dose Optimization Using Population PK for an Orphan Drug Image 1

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.

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.

Certara CS Dose Optimization Using Population PK for an Orphan Drug Image 2

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