title: Pharmacokinetic Modeling and Monte Carlo Simulation to Predict Interindividual Variability in Human Exposure to Oseltamivir and Its Active Metabolite, Ro 64-0802.
abstract: 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.
authors: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors: Mototsugu
authors: M
authors: Ito
authors: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors: Hiroyuki
authors: H
authors: Kusuhara
authors: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors: Atsushi
authors: A
authors: Ose
authors: Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
authors: Tsunenori
authors: T
authors: Kondo
authors: Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
authors: Kazunari
authors: K
authors: Tanabe
authors: Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
authors: Hideki
authors: H
authors: Nakayama
authors: Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
authors: Shigeru
authors: S
authors: Horita
authors: College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan.
authors: Takuya
authors: T
authors: Fujita
authors: Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan. ychi.sugiyama@riken.jp.
authors: Yuichi
authors: Y
authors: Sugiyama
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000081:Acetamides / Q000493:pharmacokinetics*; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism; D003198:Computer Simulation / Q000706:statistics & numerical data; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D018345:Mice, Knockout; D008954:Models, Biological; D009010:Monte Carlo Method; D009154:Mutation; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D053139:Oseltamivir / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000493:pharmacokinetics*; D011897:Random Allocation; D013045:Species Specificity; D014018:Tissue Distribution / Q000235:genetics; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000081:Acetamides; D000998:Antiviral Agents; D029362:Organic Anion Transporters, Sodium-Independent; D053139:Oseltamivir; D011355:Prodrugs; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C403132:Ro 64-0802; C114338:organic anion transport protein 3; C095122:multidrug resistance protein 3
keywords: Monte Carlo simulation; Tamiflu®; interindividual variability; pharmacokinetics