Sayo Matsuoka1, Satoko Hori2, Hiroki Satoh3, Takeshi Nagamatsu4, Tomoyuki Fujii4, Yasufumi Sawada5. 1. Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. 2. Laboratory of Drug Lifetime Management, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. 3. Laboratory of Drug Lifetime Management, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan; Interfaculty Initiative in Information Studies, The University of Tokyo, Tokyo, Japan. 4. Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 5. Laboratory of Drug Lifetime Management, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. Electronic address: sawada@mol.f.u-tokyo.ac.jp.
Abstract
INTRODUCTION: Although selective serotonin reuptake inhibitors have been used during pregnancy for the treatment of depression and anxiety disorders, the fetal plasma concentration profiles of them remained unclear. Therefore, the aim of this study was to develop a pharmacokinetic model to estimate fetal plasma concentration profiles of fluvoxamine, and to clarify the differences with those of paroxetine. METHODS: Perfusion studies using human placentae obtained from full-term pregnant women were conducted to estimate transplacental pharmacokinetic parameters for fluvoxamine. The characteristics of placental permeability were compared with those of paroxetine in our previous report. Using a developed model and these parameters, fetal plasma concentration profiles of fluvoxamine administered to mothers were simulated. RESULTS: The results of perfusion studies and transplacental transfer kinetic parameters indicated that fluvoxamine is less efficiently distributed to placental tissue than paroxetine. The model predicted a maternal-fetal plasma concentration ratio of 0.376 after repeated maternal administration of fluvoxamine, similar to the ratio for paroxetine. However, if the mother ceased taking drug, the model predicted a half-life of fluvoxamine in fetal plasma of 35 h, which is longer than that of paroxetine (10 h). We used the model to evaluate a proposed taper regimen for full-term pregnant women taking fluvoxamine that would minimize the risk of neonatal withdrawal syndrome. DISCUSSION: The obtained parameters and developed model enabled us to predict the fetal plasma concentration profiles of fluvoxamine. The risk of neonatal withdrawal syndrome due to abrupt discontinuation may be less with fluvoxamine than with paroxetine.
INTRODUCTION: Although selective serotonin reuptake inhibitors have been used during pregnancy for the treatment of depression and anxiety disorders, the fetal plasma concentration profiles of them remained unclear. Therefore, the aim of this study was to develop a pharmacokinetic model to estimate fetal plasma concentration profiles of fluvoxamine, and to clarify the differences with those of paroxetine. METHODS: Perfusion studies using human placentae obtained from full-term pregnant women were conducted to estimate transplacental pharmacokinetic parameters for fluvoxamine. The characteristics of placental permeability were compared with those of paroxetine in our previous report. Using a developed model and these parameters, fetal plasma concentration profiles of fluvoxamine administered to mothers were simulated. RESULTS: The results of perfusion studies and transplacental transfer kinetic parameters indicated that fluvoxamine is less efficiently distributed to placental tissue than paroxetine. The model predicted a maternal-fetal plasma concentration ratio of 0.376 after repeated maternal administration of fluvoxamine, similar to the ratio for paroxetine. However, if the mother ceased taking drug, the model predicted a half-life of fluvoxamine in fetal plasma of 35 h, which is longer than that of paroxetine (10 h). We used the model to evaluate a proposed taper regimen for full-term pregnant women taking fluvoxamine that would minimize the risk of neonatal withdrawal syndrome. DISCUSSION: The obtained parameters and developed model enabled us to predict the fetal plasma concentration profiles of fluvoxamine. The risk of neonatal withdrawal syndrome due to abrupt discontinuation may be less with fluvoxamine than with paroxetine.
Authors: R Greupink; A Colbers; V E Bukkems; H van Hove; D Roelofsen; J J M Freriksen; E W J van Ewijk-Beneken Kolmer; D M Burger; J van Drongelen; E M Svensson Journal: Clin Pharmacokinet Date: 2022-05-17 Impact factor: 5.577