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Journal of Clinical Pharmacology, 2004; 44:1385-1390
© 2004 the American College of Clinical Pharmacology

DRUG INTERACTIONS

Dose-Dependent Alternations in the Pharmacokinetics of Olanzapine During Coadministration of Fluvoxamine in Patients With Schizophrenia

Chih-Chiang Chiu, MD, Hsien-Yuan Lane, MD, PhD, Ming-Chyi Huang, MD, Hui-Ching Liu, MD, Michael W. Jann, PharmD, Yuen-Yi Hon, PharmD, Wen-Ho Chang, MD and Mong-Liang Lu, MD, MS

From the Laboratory of Biological Psychiatry, Taipei City Psychiatric Center, Taipei, Taiwan (Dr Chiu, Dr Huang); Department of Psychiatry, China Medical University and Hospital, Taichung, Taiwan (Dr Lane); Hung-Chi Psychiatric Hospital, Taipei, Taiwan (Dr Liu); Department of Clinical and Administrative Sciences, Southern School of Pharmacy, Mercer University, Atlanta, Georgia (Dr Jann); Clinical Pharmacokinetics Research Laboratory, Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, Maryland (Dr Hon); Department of Psychiatry, Dalin Tzu-Chi General Hospital and Tzu-Chi University, Hualien, Taiwan (Dr Chang); and Department of Psychiatry, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan (Dr Lu).

Address for reprints: Mong-Liang Lu, MD, Department of Psychiatry, Taipei Medical University-Wan Fang Hospital, No. 111, Hsin-Long Road, Sec. 3, Taipei, Taiwan.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Olanzapine, an atypical antipsychotic agent, is a substrate of the cytochrome P4501A2 (CYP1A2) enzyme. Administration of a potent CYP1A2 inhibitor (eg, fluvoxamine) may alter the pharmacokinetics of olanzapine. This study investigated the pharmacokinetic interactions between olanzapine and fluvoxamine in patients with schizophrenia. Ten male smokers were administrated a single dose of olanzapine 10 mg at baseline, followed by 2 weeks of fluvoxamine 50 mg/day and another 2 weeks of fluvoxamine 100 mg/day. Olanzapine 10 mg was given at day 10 during each fluvoxamine treatment. After pretreatment with fluvoxamine, the area under the curve, maximal plasma concentration, and half-time of olanzapine were significantly increased by 30% to 55%, 12% to 64%, and 25% to 32%, respectively. Volume of distribution and apparent clearance were significantly reduced by 4% to 26% and 26% t O 38%, respectively, after administration of fluvoxamine. Increases in area under the plasma concentration-time curve from time 0 to infinity appear to be dose dependent. Presumably, altered olanzapine pharmacokinetics are attributed to the inhibition of CYP1A2. Patients treated with the combination of olanzapine and fluvoxamine should be monitored carefully.

Key Words: Olanzapine • fluvoxamine • drug interactions • schizophrenia

Olanzapine is an atypical antipsychotic agent with broad efficacy in eliciting both the positive and negative symptoms in schizophrenia.1,2 Compared with traditional antipsychotic agents, olanzapine causes a lower incidence of extrapyramidal symptoms and minimal perturbation of prolactin levels.3,4 These advantages have led to an increasing use of olanzapine in the treatment of patients with schizophrenia. The relationship between the plasma concentration of olanzapine and the therapeutic response in patients with schizophrenia has been reported.5 The investigators suggested that a minimum threshold concentration of 23 mg/L was needed to achieve a therapeutic response.5

Olanzapine undergoes extensive biotransformation and is metabolized in humans via N-glucuronidation, allylic hydroxylation, N-oxidation, N-dealkylation, and a combination thereof.6 On the basis of studies in healthy volunteers6 and with human microsomes,7 the cytochrome P450 (CYP) system and the flavin-containing monooxygenase (FMO) system are responsible for olanzapine metabolism. The CYP1A2 forms 4'-N-desmethyl olanzapine and 7-hydroxy olanzapine, whereas 2-hydroxymethyl olanzapine is a minor metabolite, primarily formed by the polymorphic CYP2D6.7,8 The involvement of CYP3A4 and other isoforms in the formation of olanzapine metabolites was insignificant.7

The importance of CYP1A2 in the disposition of olanzapine has been demonstrated in several studies. Coadministration of carbamazepine resulted in an increase in the clearance of olanzapine, which was attributed to carbamazepine induction of CYP1A2.9 In addition, smoking, which also induces CYP1A2 activity, resulted in higher olanzapine clearance when compared with nonsmoking.2,10 The plasma olanzapine concentration closely correlated with the CYP1A2 metabolic activity,11 and about 65% of the variance in olanzapine concentration accounted for the urinary index of CYP1A2 activity.12

Of note, patients with schizophrenia are at high risk for the comorbidity with depression.13,14 Proportions of patients manifesting depression ranged from a high of 75%15 to a low of 7%.16 Antidepressants are often used concomitantly with antipsychotics for the management of depressive symptoms or negative symptoms of schizophrenia. Comedication with drugs that inhibit enzymes involved in the metabolism of olanzapine may interfere with the pharmacokinetics of olanzapine. Fluvoxamine has been shown to be a very potent inhibitor of CYP1A2 in vitro,17,18 and its inhibitory effect seems to be dose dependent.19 Thus, fluvoxamine has the potential to cause a pharmacokinetic interaction with olanzapine.

The current study was designed to characterize the full pharmacokinetic profile of olanzapine when it was given alone and with the coadministration of different doses of fluvoxamine in patients with schizophrenia. The purpose was to obtain various pharmacokinetic parameters that could provide information about the biological processes underlying the olanzapine-fluvoxamine drug interaction.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Patients
Ten patients with schizophrenia (mean ± SD, age 42.2 ± 8.6 years, range, 28-50 years; weight 59.8 ± 6.4 kg, range, 49-85 kg) signed informed consent and were enrolled in this study. Three hospitals participated in patient enrollment (Taipei City Psychiatric Center, Hung-Chi Psychiatric Hospital, and Taipei Medical University-Wan Fang Hospital). The study was approved by the institutional review board of each participating institute prior to commencement. Each patient met the DSM-IV criteria for schizophrenia, had not previously received olanzapine or fluvoxamine, and had not consumed beverages containing caffeine, alcohol, or grapefruit juice for at least 1 month prior to the study. Patients were also not taking any known CYP1A2 or CYP2D6 inducers or inhibitors. All patients were evaluated to be physically healthy by physical examination, medical history, and routine hematological, biochemical, and urinalysis tests. All subjects smoked more than 4 cigarettes per day.

Design
On the first study day at 8:00 AM, each patient received a single olanzapine 10-mg dose. Venous blood samples (10 mL) were collected in EDTA tubes and obtained prior to the dosage administration and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, 72, 84, 96, and 120 hours postdosing. The blood samples were centrifuged at 3000 rpm for 15 minutes and the separated plasma frozen at -20°C until assay. Fluvoxamine 50 mg was administered at 8:00 AM to each patient from days 6 to 19. On day 15, olanzapine 10 mg was given as a single dose. Blood samples were obtained at the same times as the first study period. Then, fluvoxamine 100 mg was administered at 8:00 AM to each patient from days 20 to 33. On day 29, olanzapine 10 mg was given as a single dose. Blood samples were also obtained at the same times as the previous 2 study periods.

The recommended dose for olanzapine in patients with schizophrenia was 5 to 20 mg/d. The recommended dose for fluvoxamine in patients with major depressive disorder was 100 to 200 mg/d. In this study, we chose the commonly prescribed doses of olanzapine and fluvoxamine.

Pharmacokinetic and Statistical Analysis
Olanzapine concentration was analyzed by high-performance liquid chromatography with electronic detection.20 The lower limit of quantification was 0.25 ng/mL using 1 mL of the plasma sample. All samples were assayed in duplicate.

Olanzapine pharmacokinetic parameters were determined with the use of noncompartmental analysis by WinNonlin 3.1 (Pharsight Corp, Mountain View, Calif). Maximal plasma concentration (Cmax) and time to reach Cmax (tmax) were determined by visual inspection of the concentration-time curve. The elimination rate constant ({lambda}z) was estimated as the slope of a linear regression of logarithm concentration versus time. Half-life was calculated as ln2/{lambda}z. The area under the plasma concentration-time curve from time 0 to infinity (AUC0-{infty}) was determined by the linear trapezoidal rule with extrapolation to infinity by dividing the last concentration measured by the elimination rate constant. The area under the concentration-time curve from time 0 to the last observed concentration (ie, 120 hours; AUC0-120) was also calculated by the linear trapezoidal rule. Apparent clearance (CL/F) was determined by dividing the dose administered by AUC0-{infty}, and the apparent volume of distribution (V/F) was calculated as the ratio of CL/F to {lambda}z.

With the exception of tmax, olanzapine pharmacokinetic parameter values were log-transformed and compared using repeated-measures analysis of variance with Statistica 6.0 (Statsoft, Inc, Tulsa, Okla). Post hoc pairwise comparisons of log-transformed pharmacokinetic parameter values between treatment arms were determined by the Tukey test. The same analyses were performed for tmax without logarithm transformation. Statistical significance was declared at P < .05.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
All subjects tolerated olanzapine and fluvoxamine well. Sedation was observed in patients after the administration of olanzapine, however. Whereas no patients (0%) experienced somnolence on day 1 of the study, 1 (10%) and 4 patients (40%) became sedated on days 15 and 29, respectively.

There was wide interindividual variability in plasma olanzapine concentrations, as depicted in the mean concentration versus time curves of olanzapine (Figure 1). Statistically significant differences were observed for all olanzapine pharmacokinetic parameters (Cmax, t1/2, V/F, CL/F, AUC0-120, and AUC0-{infty}) among the 3 treatment periods before and after the administration of fluvoxamine, except for tmax (Table I). Olanzapine Cmax after 10 days of fluvoxamine 100 mg administration was significantly higher than that after 10 days of fluvoxamine 50 mg and without prior treatment. Although the differences in tmax among the 3 treatment periods did not approach statistical significance (P = .178; Table I), there was a trend toward lower tmax when patients received prior treatment with fluvoxamine 50 mg and 100 mg.



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  		Figure 1. Mean olanzapine plasma concentration-time curves from 0 to 24 hours when olanzapine was administered alone and after fluvoxamine treatment. Symbols denote mean concentrations, and error bars denote standard deviations. Insert: Mean olanzapine log concentration-time curves from 0 to 120 hours.

 

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  		Table I Pharmacokinetic Parameter Changes in Olanzapine Before and After Coadministration With Fluvoxamine

 

Apparent clearance was highest when olanzapine was given alone and was significantly reduced with the coadministration of fluvoxamine 50 mg and 100 mg, respectively. The decrease in CL/F with the escalation dose of fluvoxamine is depicted in Figure 2. In parallel with the changes in CL/F, {lambda}z was decreased (data not shown) and t1/2 was significantly increased with fluvoxamine pretreatment. After the administration of fluvoxamine 50 mg, V/F was similar to that of single olanzapine administration, but the V/F after 10 days of fluvoxamine 100 mg treatment was significantly reduced when compared to that of olanzapine treatment alone. The AUC0-120 and the AUC0-{infty} were highest during the olanzapine-fluvoxamine 100-mg combination, followed by the olanzapine-fluvoxamine 50-mg combination and olanzapine single administration. Differences in these AUCs among the 3 treatment periods were statistically significant (P < .001). Post hoc pairwise comparisons further indicated that statistical differences in AUCs existed between different treatment arms (Table I).



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  		Figure 2. Decrease in olanzapine apparent clearance (CL/F) with escalation dose of fluvoxamine. OLZ, olanzapine; FLV, fluvoxamine.

 


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
This is the first report to describe the dose-dependent changes in olanzapine pharmacokinetics with the coadministration of fluvoxamine in Chinese patients with schizophrenia. Pharmacokinetic parameter values of single-dose olanzapine 10 mg alone in our patients appear to be slightly different from those reported by Callaghan et al2 but are comparable to those of Chinese healthy subjects.21 The slight differences in pharmacokinetic parameter values between our patients and subjects from the former report are likely due to differences in body weight, as no differences were found in weight-normalized pharmacokinetic parameters, except for weight-normalized V/F between healthy Chinese and Caucasian male subjects.21

CYP1A2 contributes to the formation of 4'-N-desmethyl olanzapine,7 and the ratio of N-desmethyl olanzapine to olanzapine has been found to correlate with olanzapine clearance.2 In this study, olanzapine CL/F after fluvoxamine pretreatment was significantly reduced by 26% to 38%, and AUC0-{infty} was significantly increased by 30% to 55%. These results are consistent with those of healthy volunteers,22,23 although the magnitude of changes is slightly smaller in our study. In contrast, olanzapine t1/2 was significantly increased when olanzapine was given with fluvoxamine 50 mg, but no such changes in t1/2 were found in the healthy volunteer study. A trend toward longer t1/2 was also found during the coadministration of fluvoxamine 100 mg and olanzapine. The change of t1/2 during this period might have been counterbalanced by the significant reduction in V/F, causing the insignificant difference in t1/2. Because olanzapine is highly protein bound, the decrease in V/F during the coadministration of fluvoxamine 100 mg might be associated with the displacement of plasma protein binding. Similar phenomena have also been observed in healthy Chinese volunteers treated with 100 mg/d fluvoxamine and a single 10-mg dose of olanzapine.23 Compared with the study of Wang et al,23 the extent of fluvoxamine-induced changes in olanzapine pharmacokinetic profiles was smaller in our study. Overall, the reduced CL/F and increased t1/2 and AUCs indicate that there was decreased metabolism and hence prolonged elimination of olanzapine. As previously suggested, this is likely to be caused predominantly by fluvoxamine-meditated CYP1A2 inhibition.

Similar to the concentration- and dose-dependent inhibition of fluvoxamine metabolism by clozapine,24-27 the interaction between olanzapine and fluvoxamine in our study appears to be dose dependent. Apparent clearance was decreased (Figure 2) and AUC0-{infty} was increased with increasing doses of fluvoxamine, with AUC0-{infty} significantly increased by a factor of 1.55 upon the addition of 100 mg fluvoxamine. These results are consistent with and supported by the dose-dependent effects of fluvoxamine on CYP1A2 activity.19 Apparently, olanzapine metabolism was affected to a lesser extent by fluvoxamine when compared to clozapine, as clozapine AUC was increased by a factor of 2.58 with the pretreatment of fluvoxamine 100 mg/d.28

Various studies have reported that age,2,29 gender,29,30 and smoking1,12,29 could influence olanzapine pharmacokinetics. However, the influence of these factors could not be assessed in our study because all of our subjects were male, smokers, and younger than 60 years old. These characteristics of our subjects might lead to relatively lower plasma olanzapine concentrations after the administration of a single dose of olanzapine. Cigarette smoking can induce CYP1A2 activity and increase the clearance of CYP1A2-metabolized drugs.31 Subjects who smoke had lower plasma concentrations of olanzapine than nonsmokers.1,12,29 Likewise, the metabolism of clozapine has also been affected by smoking.28 With clozapine monotherapy, plasma norclozapine/clozapine ratios were found to be higher in smokers than in nonsmokers.32 Inhibitory effects of fluvoxamine on clozapine metabolism were also stronger in smokers than in nonsmokers.32,33 Therefore, fluvoxamine can produce a greater decrease in norclozapine/clozapine ratios in smokers than in nonsmokers.33 We proposed that fluvoxamine might also inhibit olanzapine metabolism more vigorously in smokers than in nonsmokers.

Although the combined regimen of olanzapine and fluvoxamine was well tolerated by our subjects, there was an increased rate of somnolence during the combination therapy, which was probably caused by the higher plasma concentrations of and exposures to olanzapine. Because of this increased likelihood of adverse effects, careful monitoring of patients during the coadministration of olanzapine and fluvoxamine is warranted.

There were a few limitations in the current study. This study evaluated the effects of fluvoxamine on the pharmacokinetics of single-dose olanzapine. The effects of fluvoxamine on the steady-state pharmacokinetics of olanzapine remain to be clarified. In addition, the metabolites of olanzapine (eg, N-desmethyl olanzapine) were not determined, and this study was done in a small subset of patients. The long-term efficacy and safety of the olanzapine-fluvoxamine combination need to be further studied in larger patient populations.

In conclusion, altered olanzapine pharmacokinetics were observed during the coadministration of olanzapine and fluvoxamine in patients with schizophrenia. The inhibitory effects of fluvoxamine on olanzapine disposition appear to be dose dependent. Changes in olanzapine pharmacokinetics are presumably due to the inhibition of CYP1A2 activity. Patients who receive olanzapine-fluvoxamine coadministration should be carefully monitored.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
The authors express their appreciation to Ms Sue-Hong Lee, Ms Shaw-Tein Wu, and Ms Su-Chen Chang for their expert scientific and clinical collaborations.


   FOOTNOTES
 
Supported by grants NSC 92-2314-B-038-055 and NSC-92-2314-B-109-003 from the National Science Council and Taipei City Government, Taipei, Taiwan.

DOI: 10.1177/0091270004270291

Submitted for publication March 3, 2004; Revised version accepted August 18, 2004.


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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

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