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DOI: 10.1055/s-2004-815527
Olanzapine Plasma Concentration, Average Daily Dose, and Interaction with Co-Medication in Schizophrenic Patients
Publikationsverlauf
Received: 12.10.2000
Revised: 21.2.2001
Accepted: 24.1.2003
Publikationsdatum:
29. März 2004 (online)
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Background: Olanzapine, a thienobenzodiazepine, is one of the relatively new atypical antipsychotic drugs. The lowest threshold of effective olanzapine plasma levels in inpatient treatment is assumed to be 9 ng/ml [28]. Very little is known about the plasma concentration in patients at various oral doses of olanzapine or about the clinically relevant interactions with co-medications. Methods: In 71 schizophrenic patients (age 32.6 ± 12.1, range 18-63 years; 31 women, 40 men), plasma olanzapine levels were assessed in 377 tests by high-performance liquid chromatography (HPLC) with electrochemical detection. Fifty-six of these plasma levels were assessed while patients were receiving olanzapine as monotherapy; otherwise, the plasma levels were assessed with the patients receiving various co-medications. Results: The mean daily oral dose of olanzapine was 17.5 mg (SD = 7.0, range 5-40 mg), and the mean olanzapine plasma concentration was 54.2 ng/ml (SD 37.8 ng/ml, range 1.2-208 ng/ml). The plasma concentration of olanzapine increased linearly with the daily oral dose (r = 0.64, p < 0.001). A multiple variance analysis considering age and sex as covariables showed a significant difference in the dose-corrected plasma levels of olanzapine among 40 smokers and 31 non-smokers; age and sex did not affect the dose-corrected plasma levels. However, women received a significantly lower daily dose of olanzapine under routine clinical study conditions. No differences could be detected among the dose-corrected plasma concentration of those patients who were taken off olanzapine because they did not respond (n = 14) or because of side effects (n = 5) and those who were discharged while still on olanzapine. Under the co-medication with fluvoxamine, significantly higher dose-corrected olanzapine plasma concentrations were found than with olanzapine monotherapy, whereas significantly lower dose-corrected olanzapine plasma concentrations were detected under lithium and trimipramine co-medication. Under co-medication with amitriptyline, benperidol, carbamazepine, flupentixol, and lorazepam, the dose-corrected olanzapine plasma concentrations were no different than the plasma levels under olanzapine monotherapy. Conclusions: The relevance of therapeutic drug monitoring is emphasized with respect to the data presented and to the literature. Future studies should examine, in particular, the effects of a wider range of co-medications in a larger patient sample.
References
- 1 Aravagiri M, Ames D, Wirshing W C, Marder S R. Plasma level monitoring of olanzapine in patients with schizophrenia: determination by high-performance liquid chromatography with electrochemical detection. Ther Drug Monit. 1997; 19 307-313
- 2 Baptista T, Kin N MKNY, Beaulieu S, de Baptista E A. Obesity and related metabolic abnormalities during antipsychotic drug administration: mechanisms, management and research perspectives. Pharmacopsychiatry. 2002; 35 205-219
- 3 Beasley C M, Sanger T, Satterlee W, Tollefson G, Tran P, Hamilton S. Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacology. 1996; 124 159-167
- 4 Beasley C M, Tollefson G, Tran P, Satterlee W, Sanger T, Hamilton M S, and The Olanazapine HGAD Study G roup. Olanzapine versus placebo and haloperidol. Acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology. 1996; 14 112-123
- 5 Bergström R F, Callaghan J T, Cerimele B J. Pharmacokinetics of olanzapine in elderly and young. Pharm Res. 1995; 12 358 (suppl.)
- 6 Bever K A, Perry P J. Olanzapine: a serotonin-dopamine-receptor antagonist for antipsychotic therapy. Am J Health-Syst Pharmacists. 1998; 55 1003-1016
- 7 Brown E S, Thomas N R, Carmody T, Mahadi S, Nejtek V A. Atypical antipsychotics in bipolar and schizoaffective disorders. Pharmacopsychiatry. 2001; 34 80-81
- 8 Bymaster F P, Calligaro D O, Falcone J F, Marsh R D, Moore N A, Tye N C, Seeman P, Wong D T. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology. 1996; 14 87-96
- 9 Callaghan J T, Cerimele B J, Kassahun K J, Nyhart E H, Hoyes-Beehler P J, Kondraske G V. Olanzapine: interaction study with imipramine. J Clin Pharmacol. 1997; 37 971-978
- 10 Callaghan J T, Bergstrom R F, Ptak L R, Beasley C M. Olanzapine. Pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet. 1999; 3 177-193
- 11 Casey D E. Side effect profiles of new antipsychotic agents. J Clin Psychiat. 1996; 57 40-52
- 12 Catlow J T, Barton R D, Clemens M, Gillespie T A, Goodwin M, Swanson S P. Analysis of olanzapine in human plasma utilizing reversed-phase high-performance liquid chromatography with electrochemical detection. J Chromatogr B: Biomedical Applications. 1995; 668 85-90
- 13 Chiu J A, Franklin R B. Analysis and pharmacokinetics of olanzapine (LY170053) and two metabolites in rat plasma using reversed-phase HPLC with electrochemical detection. J Pharmaceut Biomed Anal. 1996; 14 609-615
- 14 Chouinard G, Lefko-Singh K, Teboul E. Metabolism of anxiolytics and hypnotics: benzodiazepins, buspirone, zoplicone, and zolpidem. Cell Mol Neurobiol. 1999; 19 533-552
- 15 Daniel W, Netter K J. Alteration of cytochrome P-450 by prolonged administration of imipramine and/or lithium to rats. Naunyn Schmiedebergs Arch Pharmacol. 1990; 342 234-240
- 16 Ereshefsky L. Pharmokinetics and drug interactions: update for new antipsychotics. J Clin Psychiat. 1996; 57 12-25 (suppl. 11)
- 17 Fulton B, Goa K L. Olanzapine. A review of its pharmacological properties and therapeutic efficacy in the management of schizophrenia and related psychoses. Drugs. 1997; 53 281-298
- 18 Gaertner H J, Gaertner I, Lampe D. Therapeutisches Drug-Monitoring von Clozapin und Olanzapin. Psychopharmakotherapie. 1999; 6 105-109
- 19 Kassahun K, Mattiuz E, Nyhart J rE. Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drug Metab Dispos. 1997; 25 81-93
- 20 Kelly D L, Conley R R, Tamminga C A. Differential olanzapine plasma concentrations by sex in a fixed-dose study. Schizophren Res. 1999; 40 101-104
- 21 Licht R W, Olesen O V, Friies P, Laustsen T. Olanzapine serum concentrations lowered by concomitant treatment with carbamazepine. J Clin Psychopharmacol. 2000; 20 110-112
- 22 Lucas R A, Gilfillan D J, Bergstrom R F. A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism. Eur J Clin Pharmacol. 1998; 54 639-643
- 23 Mäenpää M D, Wrighton S, Bergstrom R, Cerimele B, Tatum D, Hatcher B, Callaghan J T. Pharmacokinetic and pharmacodynamic interactions between fluvoxamine and olanzapine. Clinical Pharmacol Ther. 1998; 61 225
- 24 Naber D, Lambert M, Krausz M. Atypische Neuroleptika in der Behandlung schizophrener Patienten. Bremen; UNI-MED 1999
- 25 Nemeroff C B. Dosing the antipsychotic medication olanzapine. J Clin Psychiat Monograph. 1997; 15 24-26
- 26 Olesen O V, Linnet K. Olanzapine serum concentrations in psychiatric patients given standard doses: the influence of comedication. Ther Drug Monit. 1999; 21 87-90
- 27 Patel B R, Nyhart J rEH, Callaghan J T. Combined population pharmacokinetic analysis of olanzapine in healthy volunteers. Pharm Res. 1995; 12 360 (suppl.)
- 28 Perry P J, Sanger T, Beasley C. Olanzapine plasma concentrations and clinical response in acutely ill schizophrenic patients. J Clin Psychopharmacol. 1997; 17 472-477
- 29 Pollock B. Gender differences in psychotropic drug metabolism. Psychopharmacol Bull. 1997; 33 235-241
- 30 Ring B J, Binkley S N, Vandenbranden M, Wrighton S A. In vitro interaction of the antipsychotic agent olanzapine with human cytochromes P450 CYP2C9, CYP2C19, CYP2D6 and CYP3A. British J Clinical Pharmacol. 1996; 41 181-186
- 31 Ring B J, Catlow J, Lindsay T J, Gillespie T, Roskos L K, Cerimele B J, Swanson S P, Mitchell A, Wrighton H, Wrighton S A. Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine. J Pharmacol Exp Ther. 1996; 276 658-666
- 32 Tohen M, Chengappa K NR, Suppes T, Zarate D, Calabrese J R, Bowden C L, Sachs G S, Kupfer D J, Baker R W, Risser R C, Keeten E L, Feldman P D, Tollefson G D, Breier A. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiat. 2002; 59 62-69
- 33 Tollefson G D, Beasley C M, Tran P V, Street J S, Krueger J A, Tamura R N, Graffeo K A, Thieme M E. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiat. 1997; 154 457-465
- 34 Tollefson G D, Sanger T M, Lu Y, Thieme M E. Depressive signs and symptoms in schizophrenia. A prospective blinded trial of olanzapine and haloperidol. Arch Gen Psychiat. 1998; 55 250-258
- 35 Tollefson G D, Sanger T M. Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine. Am J Psychiat. 1997; 154 466-474
- 36 Tran P, Beasley C, Street J. Olanzapine versus haloperidol: acute results of the multi-center international trial. 20th Congress of the International College of Neuropsychopharmacology (CINP). Melbourne, Australia; 1996
- 37 Virkkunen M, Wahlbeck K, Rissanen A, Naukkarinen H, Franssila-Kallunki A. Decrease of energy expenditure cause weight increase in olanzapine treatment - a case study. Pharmacopsychiatry. 2002; 35 124-126
- 38 Weigmann H, Gerek S, Zeisig A, Müller M, Härtter S, Hiemke C. Fluvoxamine but not sertraline inhibits the metabolism of olanzapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit. 2001; 23 410-413
- 39 Yoshioka H, Ida S, Yokota M, Nishimoto A, Shibata S, Sugawara A, Takiguchi Y. Effects of lithium on the pharmacokinetics of valproate in rats. J Pharm Pharmacol. 2000; 52 297-301
Dr. med. Dipl.-Psych. Niels Bergemann
Department of Psychiatry, University of Heidelberg
Voss-Str. 4
D-69118 Heidelberg
Germany
Telefon: +49(0)6221/56-5411, -4466
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eMail: niels_bergemann@med.uni-heidelberg.de