コンドウ　ツネノリ   Kondou Tsunenori   近藤　恒徳    所属   医学部 医学科（附属足立医療センター）    職種   教授
論文種別	原著
言語種別	英語
査読の有無	査読なし
表題	Pharmacokinetic Modeling and Monte Carlo Simulation to Predict Interindividual Variability in Human Exposure to Oseltamivir and Its Active Metabolite, Ro 64-0802.
掲載誌名	正式名：The AAPS journal 略　 称：AAPS J ISSNコード：15507416/15507416
掲載区分	国外
巻・号・頁	19(1),pp.286-297
著者・共著者	Ito Mototsugu, Kusuhara Hiroyuki, Ose Atsushi, Kondo Tsunenori, Tanabe Kazunari, Nakayama Hideki, Horita Shigeru, Fujita Takuya, Sugiyama Yuichi
発行年月	2017/01
概要	Oseltamivir (Tamiflu®) is a prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase. There is a possible relationship between oseltamivir treatment and neuropsychiatric adverse events; although this has not been established, close monitoring is recommended on the prescription label. The objective of this study was to predict interindividual variability of human exposure to oseltamivir and its active metabolite Ro 64-0802. By leveraging mathematical models and computations, physiological parameters in virtual subjects were generated with population means and coefficient of variations collected from the literature or produced experimentally. Postulated functional changes caused by genetic mutations in four key molecules, carboxylesterase 1A1, P-glycoprotein, organic anion transporter 3, and multidrug resistance-associated protein 4, were also taken into account. One hundred thousand virtual subjects were generated per simulation, which was iterated 20 times with different random number generator seeds. Even in the most exaggerated case, the systemic areas under the concentration-time curve (AUCs) of oseltamivir and Ro 64-0802 were increased by at most threefold compared with the population mean. By contrast, the brain AUCs of oseltamivir and Ro 64-0802 were increased up to about sevenfold and 40-fold, respectively, compared with the population means. This unexpectedly high exposure to oseltamivir or Ro 64-0802, which occurs extremely rarely, might trigger adverse central nervous system effects in the clinical setting.
DOI	10.1208/s12248-016-9992-0
PMID	27800573