Abstract
The pharmacokinetics and tissue distribution of renadirsen sodium, a dystrophin exon-skipping phosphorothioate-modified antisense oligonucleotide with 2’-O,4’-C-ethylene-bridged nucleic acid (ENA), after subcutaneous or intravenous administration to cynomolgus monkeys were investigated. The plasma concentration of renadirsen after subcutaneous administration at 1, 3, and 10 mg/kg increased with the dose. The absolute bioavailability at 3 mg/kg after subcutaneous administration was calculated as 88.6%, and the time to reach maximum plasma concentration of renadirsen was within 4 h, indicating the efficient and rapid absorption following subcutaneous administration. The exposure of muscle tissues to renadirsen was found to increase with repeated dosing at 6 mg/kg, and higher exposure was observed in the diaphragm and heart than in the quadriceps femoris and anterior tibialis muscles. Renadirsen achieved more exon 45-skipped dystrophin mRNA in the diaphragm and heart than in the quadriceps femoris and anterior tibialis muscles. Renadirsen also showed a cumulative skipping effect in a repeated-dose study. The findings on exon 45-skipped dystrophin mRNA in these muscle tissues were consistent with the concentration of renadirsen in these tissues. Because it is not feasible to directly evaluate drug concentration and exon skipping in the heart and diaphragm in humans, the pharmacokinetics and pharmacodynamics of renadirsen in these tissues in monkeys are crucial for the design and interpretation of clinical settings.
Acknowledgments
The authors thank Shin Nippon Biomedical Laboratories, Ltd. (SNBL), for conducting the PK study and determining the plasma concentration of renadirsen. SNBL kindly supplied us with data on the weights of the body, diaphragm, quadriceps femoris, and tibialis anterior muscles of 4 to 13 cynomolgus monkeys. The authors also thank CMIC Pharma Science Co., Ltd., for determining the tissue concentration of renadirsen.
Disclosure statement
N. Yamamura, H. Takakusa, D. Asano, K. Watanabe, Y. Shibaya, R. Yamanaka, K. Fusegawa, A. Kanda, H. Nagase, K. Takaishi, and M. Koizumi are employees of Daiichi Sankyo. Co., Ltd. Y. Takeshima received consulting fees for research and development of DMD treatment from Daiichi Sankyo Co., Ltd. M. Matsuo received joint research funding and consulting fees for research and development of DMD treatment from Daiichi Sankyo Co., Ltd.