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The Differential Effects of Steady-State Fluvoxamine on the Pharmacokinetics of Olanzapine and Clozapine in Healthy Volunteers

From the Laboratory of Clinical Psychopharmacology, Beijing An Ding Hospital, Capital University of Medical Sciences, Beijing, China (Dr. Wang, Dr. Li, Y.-M. Zhai, Dr. Cai, Dr. Weng); Department of Psychiatry, First Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, China (Dr. Zhang); Research Institute of Mental Health, Xiang-Ya School of Medicine, Central South University, Changsha, Hunan, China (R.-H. Zhu, Dr. Zhao); and Pharmacogenetics Research Institute, Xiang-Ya School of Medicine, Central South University, Changsha, Hunan, China (Dr. Zhou). Drs. Chuan-Yue Wang and Zhang-Jin Zhang made equal contributions to this work.

The combination of atypical antipsychotics and selective serotonin reuptake inhibitors is an effective strategy in the treatment of certain psychiatric disorders. However, pharmacokinetic interactions between the two classes of drugs remain to be explored. The present study was designed to determine whether there were different effects of steady-state fluvoxamine on the pharmacokinetics of a single dose of olanzapine and clozapine in healthy male volunteers. One single dose of 10 mg olanzapine (n = 12) or clozapine (n = 9) was administered orally. Following a drug washout of at least 4 weeks, all subjects received fluvoxamine (100 mg/day) for 9 days, and one single dose of 10 mg olanzapine or clozapine was added on day 4. Plasma concentrations of olanzapine, clozapine, and N-desmethylclozapine were assayed at serial time points after the antipsychotics were given alone and when added to fluvoxamine. No bioequivalence was found in olanzapine alone and cotreatment with fluvoxamine for the mean peak plasma concentration (C_max), the area under the concentration-time curve from time 0 to last sampling time point (AUC_0-t), and from time 0 to infinity (AUC_0-). Under the cotreatment, C_max of olanzapine was significantly elevated by 49%, with a 32% reduced time (t_max) to C_max, whereas the C_max and t_max of clozapine were unaltered. The cotreatment increased the AUC_0-t and AUC_0- of olanzapine by 68% and 76%, respectively, greater than those of clozapine (40% and 41%). The presence of fluvoxamine also prolonged the elimination half-life (t_1/2) of olanzapine by 40% and, to a much greater extent, clozapine by 370% but reduced the total body clearance (CL/F) of clozapine (78%) more significantly than it did for olanzapine (42%). The apparent volume of distribution (V_d) was suppressed by 31% in olanzapine combined with fluvoxamine but was unaltered in the clozapine regimen. A significant reduction in the N-desmethylclozapine to clozapine ratio was present in the clozapine with fluvoxamine regimen. The effects of fluvoxamine on different aspects of pharmacokinetics of the two antipsychotics may have implications for clinical therapeutics.

Key Words: Fluvoxamine • olanzapine • clozapine • pharmacokinetics • healthy volunteers

Address for reprints: Chuan-Yue Wang, MD, PhD, Laboratory of Clinical Psychopharmacology, Beijing An Ding Hospital, Capital University of Medical Sciences, 5 Ankang Hutong Road, Xicheng District, Beijing 100088, China.

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