On receiving the Best Poster Award
Research Pharmacokinetics Laboratory, Takeda Pharmaceutical Company Limited
I am pleased to present my poster entitled “Advanced physiologically-based pharmacokinetic model for transferrin receptor-mediated drug delivery system into brain in rats, monkeys and human transferrin receptor knock-in mice”. Thank you very much for the award of “Best Poster Award” for the presentation entitled “Advanced physiologically-based pharmacokinetic model for transferrin receptor-mediated drug delivery system into brain in rats, monkeys and human transferrin receptor knock-in mice”. I would like to express my sincere gratitude to the selection committee members and all the people involved in the Japanese Society of Pharmacokinetics and Pharmacodynamics for reviewing my presentation.
In drug discovery targeting central nervous system diseases, one of the most important issues is to design molecules that can efficiently penetrate the blood-brain barrier (BBB) and deliver them to brain parenchymal cells, not only small molecules but also macromolecular modalities . Transferrin receptor (TfR)-mediated transcytosis is known as an attractive pathway for the delivery of macromolecular modalities across the BBB to the central nervous system. JR-141, a fusion protein of an anti-human TfR antibody and iduronic acid 2-sulfatase, has already been successfully launched as a treatment for mucopolysaccharidosis type II with promising results in clinical trials [2-4]. Following this success, clinical trials are underway for subsequent molecules , and the development of next-generation drugs based on TfR-mediated delivery systems is gaining momentum. However, the drug profile for efficient TfR-mediated drug delivery is not fully understood. In this study, we developed a physiologically-based pharmacokinetic (PBPK) model to provide direction for TfR-mediated drug delivery systems. This model addresses the TfR-mediated transcellular and intracellular transport of anti-TfR antibodies into brain capillaries, brain endothelial cells, extracellular fluid (ECF), and brain parenchymal cells (BPCs). The model was calibrated using previously published data on brain and plasma concentrations in rats, monkeys, and human TfR knock-in (hTfR-KI) mice, and a PBPK model was constructed to predict brain concentration transitions with good accuracy in these three animal species. Next, sensitivity analysis was performed to estimate the optimal characteristics of TfR-mediated drug delivery, and the results showed: 1) a bell-shaped relationship between TfR-Kd and brain exposure, 2) the optimal range of TfR-Kd to maximize brain exposure was close in monkeys and hTfR-KI mice, but different in rats, and 3) the optimal range of TfR-Kd to maximize brain exposure was different in rats. TfR-Kd required to maximize exposure in BPCs is smaller than that in ECF, and 4) the use of pH-sensitive antibodies increases exposure in BPCs, while the effect of increasing exposure in ECF is limited. These results will contribute to the efficient and optimal molecular design of macromolecular modalities utilizing TfR-mediated delivery technology, although further support based on experimental data will be required in the future. Finally, I would like to express my sincere appreciation for the award.
Finally, I would like to express my sincere appreciation to the many people who have contributed to this award. I am grateful to Professor Hiroyuki Kusuhara and Dr. Takaki Okita of the Department of Molecular Pharmacokinetics and Pharmacodynamics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, and all the members of the Research Pharmacokinetics Laboratory of Takeda Pharmaceutical Company Limited, especially Dr. Liu Si-yu, Dr. Akihiko Goto, Dr. Shunsuke Yamamoto, Dr. Hideki Hirabayashi, Laboratory Director, Dr. Shinji Iwasaki, Research Manager, Dr. Hiroko Hishinuma, Dr. Miyu Nakayama, Dr. Finally, I would like to take this opportunity to thank my family for providing me with an environment in which I can devote myself to my work.