N. Bergemann1 Olanzapine Plasma Concentration, Average Daily A. Frick1 Dose, and Interaction with Co-Medication in P. Parzer2 J. Kopitz3 Schizophrenic Patients rgnlPaper Original

Background: Olanzapine, a , is one of the fect the dose-corrected plasma levels. However, women received relatively new atypical drugs. The lowest threshold a significantly lower daily dose of olanzapine under routine clin- of effective olanzapine plasma levels in inpatient treatment is as- ical study conditions. No differences could be detected among sumed to be 9 ng/ml [28]. Very little is known about the plasma the dose-corrected plasma concentration of those patients who concentration in patients at various oral doses of olanzapine or were taken off olanzapine because they did not respond about the clinically relevant interactions with co-medications. 5n=14) or because of side effects 5n=5) and those who were Methods: In 71 schizophrenic patients 5age 32.6  12.1, range discharged while still on olanzapine. Under the co-medication 18±63 years; 31 women, 40 men), plasma olanzapine levels with , significantly higher dose-corrected olanza- were assessed in 377 tests by high-performance liquid chroma- pine plasma concentrations were found than with olanzapine tography 5HPLC) with electrochemical detection. Fifty-six of monotherapy, whereas significantly lower dose-corrected olan- these plasma levels were assessed while patients were receiving zapine plasma concentrations were detected under and olanzapine as monotherapy; otherwise, the plasma levels were co-medication. Under co-medication with amitrip- assessed with the patients receiving various co-medications. tyline, , , , and , Results: The mean daily oral dose of olanzapine was 17.5 mg the dose-corrected olanzapine plasma concentrations were no 5SD = 7.0, range 5±40 mg), and the mean olanzapine plasma different than the plasma levels under olanzapine monotherapy. concentration was 54.2 ng/ml 5SD 37.8 ng/ml, range 1.2±208 ng/ Conclusions: The relevance of therapeutic drug monitoring is 63 ml). The plasma concentration of olanzapine increased linearly emphasized with respect to the data presented and to the litera- with the daily oral dose 5r=0.64, p < 0.001). A multiple variance ture. Future studies should examine, in particular, the effects of a analysis considering age and sex as covariables showed a signifi- wider range of co-medications in a larger patient sample. cant difference in the dose-corrected plasma levels of olanzapine among 40 smokers and 31 non-smokers; age and sex did not af-

Introduction in comparison with [3,4,33]. Furthermore, like the other atypical neuroleptics, olanzapine has the advantage over Olanzapine is a relatively new atypical neuroleptic from the the classic neuroleptics not only of being effective in treating group of and is considered to be highly the positive symptoms such as delusions and hallucinations but effective in treating . Its antipsychotic efficacy has also of having a therapeutic effect on the negative symptoms, been well substantiated in placebo-controlled studies as well as such as marked apathy and language poverty, and on affective

Affiliation 1 Department of Psychiatry, University of Heidelberg 2 Department of Child- and Adolescent Psychiatry, University of Heidelberg 3 Institute of Pathochemistry and General Neurochemistry, University of Heidelberg

Correspondence Dr. med. Dipl.-Psych. Niels Bergemann ´ Department of Psychiatry, University of Heidelberg ´ Voss-Str. 4 ´ D-69118 Heidelberg ´ Germany ´ Phone: +4950)6221/56-5411, -4466 ´ Fax: +4950)6221/56-5477 ´ E-Mail: [email protected]

Received 12.10.2000 ´ Revised 21.2.2001 ´ Accepted 24.1.2003 Bibliography Pharmacopsychiatry 2004; 37: 63±68 ´  Georg Thieme Verlag Stuttgart ´ New York ´ ISSN 0176-3679 ´ DOI 10.1055/s-2004-815527 and cognitive disturbances [34,35]. In comparison with the con- Methods ventional neuroleptics, significantly fewer extrapyramidal side effects are present. In addition, there are far fewer changes in Study sample the EEG than with , a lower incidence of orthostatic hy- Altogether, 377 olanzapine plasma levels were determined at potonia, no influence on the QTc interval, and a mostly transient regular intervals in 71 inpatients being treated at the Depart- increase in transaminase and prolactin levels similar to those of ment of Psychiatry at the University of Heidelberg 5age mean  clozapine 5cf. [11,24]). However, a higher rate of side effects such SD: 32.6  12.1, range 18±63 years, 31 women, 40 men). The pa- as dryness of the mouth, increase in appetite, and tients were receiving olanzapine to treat either a schizophrenic were found [2,17,37]. Preliminary findings have shown that 5ICD 10: F20.0±20.9) or an affective schizophrenic dis- olanzapine is superior to haloperidol in preventing relapse [36]. order 5ICD 10: F25.0±25.9). Of the patients, 31 were smokers and The recommended starting dose is 10 mg/day; further adjust- 40 were non-smokers. For each patient up to 23 tests were car- ment of the daily dose is recommended according to the individ- ried out, and the mean number of plasma levels assessed for ual's clinical features [25]. each patient was 5.3. rgnlPaper Original The chemical structure and receptor-binding profile of olanza- As with typical groups of schizophrenic inpatients, the women

pine are similar to that of clozapine. Olanzapine has D4-receptor were significantly older than the men 5age mean  SD: 36.5 

affinity as well as relatively strong anti-alpha1- and 14.1 vs. 29.5  9.5; t-test: t=±2.47, p=0.016) and the men antihistaminergic properties, which account for the sedating ef- were smokers significantly more often than the women 555% fect. In vitro data suggest that the effects of olan- smokers in men vs. 29% smokers in women, c2 = 4.78, df = 1, zapine are similar to those of clozapine 5cf. [8]). In vivo, olanza- p=0.029). Furthermore, smokers were significantly younger pine produces fewer adverse anticholinergic side effects than than non-smokers, regardless of the sex 5ANOVA of age with fac- clozapine. tors smoking and sex, effect of factor smoking: F=6.22, df = 1, p=0.015). To date, little is known about the significance of plasma concen- trations of olanzapine for therapy or about the correlation with Fifty-six olanzapine plasma levels were assessed while patients clinical efficacy. By applying the statistical procedure of a recei- were receiving olanzapine as monotherapy; otherwise, the plas- ver-operating characteristic 5ROC) curve analysis, Perry et al. [28] ma levels were assessed with the patients receiving various co- suggested that the therapeutic range is above 9 ng/ml. Under medications 5n=321). Fifty-two patients were discharged with clinical conditions there is a broad inter-individual variability of olanzapine as medication. In 14 patients olanzapine treatment the dose-corrected plasma levels with therapeutic dose regi- was discontinued because of being ineffective and in five pa- mens [18]. This variability may be the result of different factors, tients, because of adverse side effects 5weight gain in three cases among which are the influence of age, sex, and cigarette smoking and in two cases).

64 and the effect of different co-medications. Blood specimens and laboratory analysis The of olanzapine lies between 80% and 100%. Blood specimens were taken between 08:00 and 09:00 a.m., The rate of protein binding is 93%, whereby olanzapine usually i. e., 10±24 h after the last oral dose of olanzapine in steady state

binds to albumin and a1-acid glycoprotein. Absorption occurs 5the daily dose had not been changed for at least 7 days). The soon after oral intake, and the maximum plasma concentration plasma olanzapine levels were determined using high-per- is reached after approximately 5 hours. Food intake has no ef- formance liquid chromatography 5HPLC) with electrochemical fect on absorption [16]. More than 80% of olanzapine is meta- detection. The method was adapted from published procedures bolized to numerous products [19], mainly via the enzymes [12,13]. Samples 51 ml plasma) were diluted with an equal vol- CYP1A2 and CYP2D6, but also via CYP3A4 of the cytochrome ume of SPE buffer 5100 mM ascorbic acid/50 mM potassium P450 system and through formation of N-glucuronides. Olanza- phosphate buffer, pH 6.0) and applied to a bonded-silica solid- pine-10-N-glucuronide is the major metabolite; less abundant phase extraction column 5Bond Elut Certify, Varian, Harbor ones are olanzapine-4¢-N-oxide and 4¢-N-desmethylolanzapine City, USA). The column then was washed by the successive ap- [30,31]. In humans, metabolites are excreted into the urine; plication of 5 ml SPE buffer, 1 ml methanol/borate buffer pH 10 however, even severe renal damage does not affect olanzapine 53:7; v/v), 1 ml 1 M acetic acid, and 5 ml methanol. Finally, [10]. olanzapine was eluted with 3 ml ethyl acetate/1 M ammonium hydroxide 597: 3; v/v). The eluate was evaporated in a stream of The aim of the present investigation was to elucidate the factors nitrogen and the remainder was re-dissolved in 0.5 ml mobile that affect olanzapine levels in schizophrenic patients. For this phase and separated by HPLC on a Hypersil C18 column 55 mm purpose, the following questions were addressed: particle size, dimension: 250”4.6 mm, Varian) at 458C. The

± What ranges of olanzapine plasma concentrations are found mobile phase constituted of H2O/methanol/acetonitrile/tri- when therapy is guided by clinical impression? ethylamine 54 : 5:1 : 0,02; v/v/v/v; pH adjusted to 7.0 with phos- ± How do the daily dose and the plasma levels of olanzapine phoric acid) and the flow rate was 0.2 ml/min. Olanzapine was correlate? detected electrochemically 5electrochemical detector: ESA ± How do the variables age, sex, cigarette consumption, and var- Coulochem II; Chelmsford, USA [1]), then the guard cell was ious co-medications affect the olanzapine plasma concentra- set to ±300 mV and the analytical cell to 200 mV and quantified tion? by internal standardization; the internal standard LY170222 was obtained from Eli Lilly.

Bergemann N et al. Olanzapine Plasma Concentration ¼ Pharmacopsychiatry 2004; 37: 63±68 The assay was validated by spiked human plasma samples. The 5n=71, p < 0.001) indicates a linear relationship between the detection limit was 2 ng/ml. Linear calibration curves were ob- mean daily dose of olanzapine and the mean plasma concentra- tained in the concentration range 2±200 ng/ml with coefficients tion per patient 5Fig.1). of determination higher than 0.9924. The intra-assay precision was determined by analyzing five spiked plasma samples at dif- No significant difference was found among patients in whom ferent concentrations, ranging from 5 to 200 ng. Intra-assay ac- olanzapine had been discontinued because of non-response curacy was always between 95% and 108%, and intra-assay pre- 5n=14) or side effects 5n=5) and those who were still receiv- cision was always better than 8%. Inter-assay accuracy deter- ing the drug upon discharge from the hospital 5n=52) regarding mined with spiked plasma samples 5n=5) over 3 days at 5, 50, the mean plasma level 5ANOVA: F=0.1, df = 2, p=0.9), the and 200 ng/ml ranged between 96% and 103%. The extraction ef- mean daily olanzapine dose 5ANOVA: F=0.14, df = 2, ficiency was calculated as the ratio of the peak height of the ana- p=0.87), or the mean dose-corrected plasma concentrations lytes from extracted plasma standards to standards of the same 5ANOVA: F=0.17, df = 2, p=0.84). concentrations prepared in the mobile phase. Averaged extrac-

tion efficiency was 69.2%, 74.1%, and 76.1% at 5, 50, and 200 ng/ Effects of age,sex,and cigarette smoking on the plasma Paper Original ml, respectively. concentration Considering the interdependence of the relevant variables ± for Interference of the assay with co-medications was excluded in example, smoking behavior is different in men and women control experiments using spiked plasma samples. 5women: 9 smokers, 22 non-smokers; men: 22 smokers, 18 non-smokers) and is less frequent in older age ± a multiple var- Biometrics iance analysis 5ANOVA) was carried out to determine whether In addition to descriptive statistics, an analysis of variance 5ANOVA) age, sex, and cigarette smoking affected the plasma concentra- was carried out for inference statistical evaluation of the effects of tion 5overall F=3.55, df = 4, p=0.11, R2 = 0.177). A significant age, sex, and cigarette smoking as independent variables on the difference in the dose-corrected plasma levels of olanzapine was olanzapine plasma concentration. An ANOVA was also used for found between smokers and non-smokers 5F=11.86, df = 1, the comparison of the dose-corrected olanzapine plasma concen- p=0.001); however, age 5F=0.02, df = 1, p=0.89) and sex trations in different subgroups of the sample 5patients who were 5F=0.8, df = 1, p=0.37) had no influence on the dose-correc- taken off olanzapine because of non-response or adverse side ted plasma levels of olanzapine. There was no interaction be- effects and those who were discharged with olanzapine). tween sex and smoking behavior 5F=0.02, df = 1, p=0.88).

For testing the effects of various co-medications on the dose-cor- Effects of various co-medications on the olanzapine plasma rected olanzapine plasma concentration, a random-effects re- concentration gression analysis was carried out. The correlation coefficient Olanzapine plasma levels were assessed either while the pa- was used for bivariate analysis of the relation between olanza- tients were receiving olanzapine as monotherapy 5n=56) or in 65 pine daily dose and plasma level. combination with various co-medications 5n=321). The mean dose-corrected olanzapine plasma concentration under mono- The dose-corrected olanzapine plasma levels were checked by therapy was 3.03 5SD = 1.5). the Shapiro-Wilk test for normal data. However, neither the dose-corrected values nor the logarithmic transformed data The effects of , benperidol, carbamazepine, flupen- showed a Gaussian distribution until the fourth root of the tixol, fluvoxamine, lithium, lorazepam, and trimipramine on the dose-corrected plasma level was reached. Because this transfor- plasma concentration of olanzapine were evaluated by means of mation lacks meaningful interpretation and because none of the a random-effect regression analysis considering the influence of calculations with transformed variables produced results that were qualitatively different from those with non-transformed dose-corrected values, non-transformed, dose-corrected values were used in all calculations.

For analyzing the effect of the various co-medications, we used all individual measurements 5n=377); for all other analyses the mean daily dose and the mean 5raw and corrected) plasma levels for the measurements of each patient were calculated 5n=71).

Results

The mean daily dose of olanzapine was 17.5 mg/day 5SD 7.0 mg/ day, range 5±40 mg/day; n=377), and the mean olanzapine plasma concentration was 54.2 ng/ml 5SD 37.8 ng/ml, range 1.2±208.0 ng/ml; dose-corrected plasma concentration: mean Fig. 1 Correlation between daily dose and plasma concentrations of  SD = 3.1  1.8 ng/ml:mg; n=377). The correlation of r=0.64 olanzapine r=0.64, p < 0.001; n=71).

Bergemann N et al. Olanzapine Plasma Concentration ¼ Pharmacopsychiatry 2004; 37: 63±68 smoking behavior as co-variable 5Table 1). These psychotropic from 0.2 to 9.9 ng/ml:mg 5plasma concentration 54.2  37.8, drugs were administered in at least more than five patients of range 1.2±208.0 ng/ml) at an average daily drug dose of 17.5  the sample. 7.0 mg 5range 5±40 mg/day).

A significantly higher plasma level of olanzapine became evident We found significantly lower dose-corrected plasma concentra- under the co-administration of fluvoxamine, while there was a tions of olanzapine in smokers than in non-smokers. This finding significantly lower olanzapine plasma level under co-medication is in good agreement with the notion of the induction of CYP1A2 with trimipramine and lithium. by smoking and is in line with findings of Patel et al. [27], who demonstrated a considerably reduced olanzapine elimination The ªother medicationsº included psychotropic drugs, which half-life and an increased clearance in smokers. were administered less frequently in these patients, and a variety of medications for the treatment of internal medical conditions No effect of age on the plasma concentration was seen that could 5biperiden, , , , , pipam- be considered as being in line with results of a study in 44 pa-

rgnlPaper Original perone, , , , clozapine, halo- tients with schizophrenia who were older than age 65 and who peridol, , , , , prome- received doses between 5 and 20 mg/day and that was not asso- thazine, L-thyroxine, piretanide, nevirapine, acetylsalicylic acid, ciated with any different profile of adverse events compared fluvastatin, omeprazole, ± in the order of numbers of with younger patients 5Lilly, basic scientific information 1998). cases). Twenty-nine other medications were administered fewer However, in a study by Bergström et al. [5] 5cf. [17] and see [6] than four times each in this sample. for review), the elimination half-life of olanzapine was demon- strated to be significantly longer in healthy, older study subjects than in younger ones 548.8±54.9 vs. 29.0±38.6 h in a group of Discussion healthy study subjects over 65 years as compared to 20- to 41- year-old subjects). This was expected. As to the question of age An important result of the study is the replication of a linear and effects on the plasma concentration of olanzapine, in our sample, dose-proportionate relationship between daily dose and plasma the age distribution was skewed to the left ±50% of the patients concentrations of olanzapine, as Aravagiri et al. [1] and Kelly et were younger than 28, and 75% were younger than 40. None of al. [20] also found. our patients was over 65.

However, little experience with therapeutic drug monitoring of A longer elimination half-life of olanzapine 538.6±54.9 vs. 29.0± olanzapine in inpatients has been reported to date. As men- 48.8 h; Lilly, Basic Scientific Information 1998) and lower plasma tioned, Perry et al. [28] consider plasma concentrations of 9 ng/ clearance were found in women than in men [10,17], and higher ml as the lowest therapeutic level in acutely psychotic patients. plasma concentrations of olanzapine may be plausible, consider-

66 Gaertner et al. [18] found an average plasma concentration of ing the slower metabolism through the isoenzyme CYP1A2 [29] olanzapine of 78.3 ng/ml in 26 inpatients. Olesen and Linnet and the lower volume of distribution in women [20]. However, [26] recommend levels of 25±150 nmol/l 58±47 ng/ml) as being no significant sex difference could be found in the present study, therapeutically effective, and 80 % of the plasma olanzapine lev- either in the whole study sample or in smokers and non-smo- els determined were in this range. kers. In the group of patients who continued taking olanzapine after discharge, a sex difference could not be found after longer In the present study the mean dose-corrected plasma concentra- drug exposure, either. These findings are in contrast to those of tion of olanzapine was 3.1 ng/ml:mg 5SD 1.8 ng/ml:mg), ranging Kelly et al. [20]: although they did not discover a sex difference

Table 1 Olanzapine plasma concentrations in combination with various co-medications1

Co-medication Coefficient Standard error p 95 % confidence interval

Smoking ±1.191 0.333 < 0.001 ±1.844 ±0.538 Amitriptyline 0.059 0.324 0.856 ±0.575 0.693 Benperidol ±0.442 0.365 0.225 ±1.157 0.273 Carbamazepine ±0.402 0.435 0.356 ±1.255 0.451 Flupentixol 0.204 0.359 0.570 ±0.500 0.908 Fluvoxamine 2.266 0.430 < 0.001 1.423 3.109 Lithium ±0.890 0.369 0.016 ±1.613 ±0.167 Lorazepam ±0.518 0.344 0.132 ±1.192 0.156 Trimipramine ±0.832 0.334 0.013 ±1.487 ±0.177 Other medications 0.274 0.208 0.187 ±0.133 0.682 Constant 3.699 0.285 < 0.001 3.141 4.257

1 Results of the random-effects regression 377 measurements, 71 patients, within subject R2 = 0.13, between subject R2 = 0.21). The constant is the mean dose-corrected olanzapine plas- ma concentration for non-smokers without any co-medication. The other coefficients are differences of the mean from the constant as the result of smoking and/or co-medication.

Bergemann N et al. Olanzapine Plasma Concentration ¼ Pharmacopsychiatry 2004; 37: 63±68 in the first 3 weeks of therapy, they found significantly higher els tended to be lower under co-medication with carbamazepine. plasma concentrations in women after 5 weeks that had in- This is in contrast to the findings of Olesen and Linnet [26], who creased even more after 8 weeks. reported a 30% reduction in the plasma concentrations of olan- zapine with carbamazepine as co-medication, and to the results Regarding the interactions with co-medications, a significant ef- of Lucas et al. [22]. Licht et al. [21] demonstrated an increase in fect of fluvoxamine, trimipramine, and lithium was found on the the olanzapine plasma concentration after discontinuing carba- olanzapine plasma concentration. With fluvoxamine, a potent mazepine. inhibitor of CYP1A2, an increase of about 74% was seen in dose- corrected plasma olanzapine concentrations. This finding is in Not only smoking habits but also, most importantly, combina- accordance with the results of Mäenpää et al. [23], who assume tion therapy required by many psychiatric patients represent an increase of more than 80 % in olanzapine plasma concentra- possible causes of the changes in plasma concentrations of olan- tion under co-medication with fluvoxamine, while Weigmann zapine. By regular therapeutic drug monitoring, changes in drug et al. [38] found a 2.3-fold increase in olanzapine plasma concen- plasma concentrations can be recognized. Decreasing levels may

trations under the co-administration of fluvoxamine but no ef- lead to an exacerbation of psychotic symptoms, whereas increas- Paper Original fect of sertraline. ing levels may provoke undesired side effects, thus affecting pa- tient compliance. For this reason, therapeutic drug monitoring is The chemical structure of the trimipra- recommended for olanzapine treatment. Future studies should mine is very closely related to that of . Consequently, aim particularly at further clarifying the effects of various co- the metabolic pathways leading to biotransformation and elimi- medications in larger patient samples by making intra-individ- nation of trimipramine resemble those of imipramine [14]. In a ual comparisons and strictly controlling further influencing vari- study on between olanzapine and imipramine, ables. plasma levels of olanzapine were found to be significantly re- duced under co-medication with imipramine. 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