The differential effects of steady-state fluvoxamine on the pharmacokinetics of olanzapine and clozapine in healthy volunteers.
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- infinity )). 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- infinity ) 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.
Wang
Chuan-Yue
CY
Laboratory of Clinical Psychopharmacology, Beijing An Ding Hospital, Capital University of Medical Sciences, 5 Ankang Hutong Road, Xicheng District, Beijing 100088, China.
Zhang
Zhang-Jin
ZJ
Li
Wen-Biao
WB
Zhai
Yi-Min
YM
Cai
Zhuo-Ji
ZJ
Weng
Yong-Zhen
YZ
Zhu
Rong-Hua
RH
Zhao
Jing-Ping
JP
Zhou
Hong-Hao
HH
D000328:Adult; D000928:Antidepressive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D019540:Area Under Curve; D001569:Benzodiazepines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D003024:Clozapine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D016666:Fluvoxamine / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D000077152:Olanzapine
D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D001569:Benzodiazepines; C058272:norclozapine; D003024:Clozapine; D000077152:Olanzapine; D016666:Fluvoxamine