N. Bergemann1 Olanzapine Plasma Concentration, Average Daily A. Frick1 Dose, and Interaction with Co-Medication in P. Parzer2 J. Kopitz3 Schizophrenic Patients Original Paper Background: Olanzapine, a thienobenzodiazepine, is one of the fect the dose-corrected plasma levels. However, women received relatively new atypical antipsychotic 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 fluvoxamine, 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 lithium and olanzapine as monotherapy; otherwise, the plasma levels were trimipramine co-medication. Under co-medication with amitrip- assessed with the patients receiving various co-medications. tyline, benperidol, carbamazepine, flupentixol, and lorazepam, 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 haloperidol [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 thienobenzodiazepines and is considered to be highly the positive symptoms such as delusions and hallucinations but effective in treating schizophrenia. 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 clozapine, 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 weight gain tients were receiving olanzapine to treat either a schizophrenic were found [2,17,37]. Preliminary findings have shown that psychosis 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. Original Paper 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-adrenergic 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 anticholinergic 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 somnolence in two cases). 64 and the effect of different co-medications. Blood specimens and laboratory analysis The bioavailability 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, clearance [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: 2504.6 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.