Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
Multicentre trials in patients with schizophrenia confirm that olanzapine is a novel antipsychotic agent with broad efficacy, eliciting a response in both the positive and negative symptoms of schizophrenia. Compared with traditional antipsychotic agents, olanzapine causes a lower incidence of extrapyramidal symptoms and minimal perturbation of prolactin levels. Generally, olanzapine is well tolerated.
The pharmacokinetics of olanzapine are linear and dose-proportional within the approved dosage range. Its mean half-life in healthy individuals was 33 hours, ranging from 21 to 54 hours. The mean apparent plasma clearance was 26 L/h, ranging from 12 to 47 L/h. Smokers and men have a higher clearance of olanzapine than women and nonsmokers.
After administering [14C]olanzapine, approximately 60% of the radioactivity was excreted in urine and 30% in faeces. Olanzapine is predominantly bound to albumin (90%) and α1-acid glycoprotein (77%). Olanzapine is metabolised to its 10- and 4′- N-glucuronides, 4′-N-desmethylolanzapine [cytochrome P450 (CYP) 1A2] and olanzapine N-oxide (flavin mono-oxygenase 3). Metabolism to 2-hydroxymethylolanzapine via CYP2D6 is a minor pathway. The 10-N-glucuronide is the most abundant metabolite, but formation of 4′-N-desmethylolanzapine is correlated with the clearance of olanzapine.
Olanzapine does not inhibit CYP isozymes. No clinically significant metabolic interactions were found between olanzapine and diazepam, alcohol (ethanol), imipramine, R/S-warfarin, aminophylline, biperiden, lithium or fluoxetine. Fluvoxamine, an inhibitor of CYP1A2, increases plasma concentrations of olanzapine; inducers of CYP1A2, including tobacco smoke and carbamazepine, decrease olanzapine concentrations.
Orthostatic changes were observed when olanzapine and diazepam or alcohol were coadministered. Pharmacodynamic interactions occurred between olanzapine and alcohol, and olanzapine and imipramine, implying that patients should avoid operating hazardous equipment or driving an automobile while experiencing the short term effects of the combinations.
Individual factors with the largest impact on olanzapine pharmacokinetics are gender and smoking status. The plasma clearance of olanzapine generally varies over a 4-fold range, but the variability in the clearance and concentration of olanzapine does not appear to be associated with the severity or duration of adverse effects or the degree of efficacy. Thus, dosage adjustments appear unnecessary for these individual factors. However, dosage modification should be considered for patients characterised by a combination of factors associated with decreased oxidative metabolism, for example, debilitated or elderly women who are nonsmokers.
- Moore, N.A., Calligaro, D.O., Wong, D.T. (1993) The pharmacology of olanzapine, and other new antipsychotic agents. Curr Opin Invest Drugs 2: pp. 281-93
- Casey, D.E. What makes a neuroleptic atypical?. In: Meltzer, H.Y. eds. (1992) Novel antipsychotic drugs. Raven, New York, pp. 241-51
- Meltzer, H.Y. The mechanism of action of clozapine in relation to its clinical advantages. In: Meltzer, H.Y. eds. (1992) Novel antipsychotic drugs. Raven, New York, pp. 1-13
- Fuller, A., Snoddy, H.D. (1992) Neuroendocrine evidence for antagonism of serotonin and dopamine receptors by olanzapine (LY170053) an antipsychotic drug candidate. Res Commun Chem Pathol Pharmacol 77: pp. 87-93
- Bymaster, F.P., Calligaro, D.O., Falcone, J.F. (1996) Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14: pp. 87-96 CrossRef
- Corbett, R., Camacho, F., Woods, A.T. (1995) Antipsychotic agents antagonize non-competitive N-methyl-D-aspartate antagonist-induced behaviors. Psychopharmacology (Berl) 120: pp. 67-74 CrossRef
- Beasley, C.M. (1997) Efficacy of olanzapine: an overview of pivotal clinical trials. J Clin Psychiatry Monogr 15: pp. 16-8
- Tollefson, G.D., Beasley, C.M., Tamura, R.N. (1997) Blind, controlled, long-term study of the comparative incidence of treatment-emergenttardive dyskinesia with olanzapine or haloperidol. Am J Psychiatry 154: pp. 1248-54
- Bergstrom RF, Callaghan JT, CErimele BJ, et al. Biopharmaceutics integrated: summary volume. Lilly Laboratory for Clinical Research. Eli Lilly and Co., 155. (Data on file).
- Bergstrom, R.F., Callaghan, J.T., Cerimele, B.J. (1995) Pharmacokinetics of olanzapine in elderly and young. Pharm Res 12: pp. S-358
- Nyhart Jr EH, Cerimele BJ, Kassahun K, et al. Olanzapine: an initial assessment of the bioequivalence of capsules and tablet formulations [abstract no. 8355]. 10th Annual Meeting and Exposition, American Association of Pharmaceutical Scientists; 1995 Nov 5–9; Miami Beach (FL).
- Bergstrom RF, Cerimele BJ, et al. Olazapine in subjects with and without renal failure. Lilly Laboratory for Clinical Research. Eli Lilly and Co., 1996. (Data on file).
- Callaghan JT, Bergstrom RF, Cerimele BJ, et al. Oral olanzapine: safety and pharmacokinetic study in elderly. Lilly Laboratory for Clinical Research. Eli Lilly and Co., 1995. (Data on file).
- Thomasson HR, Callaghan JT, Bergstrom RF, et al. Oral olanzapine: safety and pharmacokineticstudy in subjects with cirrhosis. Lilly Laboratory for Clinical Research. Eli Lilly and Co., 1996. (Data on file).
- Kisicki JC, Bergstrom RF, Cerimele BJ, et al. Olanzapine: bioequivalence of capsule and tablet formulations. Lilly Laboratory for Clinical Research. Eli Lilly and Co., 1995. (Data on file).
- Henry DP, Nyhart Jr EH. LY 170 053: dose proportionality and effect of feeding on bioavailability. Lilly Laboratory for Clinical Research. Eli Lilly and Co., 1995. (Data on file).
- Bergstrom RF, Cerimele BJ, Callaghan JT, et al. Oral olanzapine: safety and pharmacokinetic study in Asians. Lilly Laboratory for Clinical Research. Eli Lilly and Co., 1997. (Data on file).
- Malituz EL, Cerimele BJ, Ptak L. Olanzapine: safety and pharmacokinetic studies on patients with cirrhosis — olanzapine excretion addendum. Lilly Laboratory for Clinical Research. Eli Lilly and Co., 1997. (Data on file).
- Kassahun, K., Mattiuz, E., Nyhart, E. (1997) Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drug Metab Dispos 25: pp. 81-93
- Ring, B.J., Catlow, J., Lindsay, T.J. (1996) 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 276: pp. 658-66
- Kassahun K. Olanzapine, N-desmethyl olanzapine and 10-N-glucuronide of olanzapine in plasma from patients on olanzapine. Indianapolis: Eli Lilly and Co., 1995 (Data on file).
- Patel BR, Kurtz DL. Population pharmacokinetic analyses of olanzapine. Indianapolis: Eli Lilly and Co., 1995 (Data on file).
- Ring, B.J., Binkley, S.N., Vandenbranden, M. (1996) In vitro interaction of the antipsychotic agent olanzapine with human cytochromes P450 CYP2C9, CYP2C19, CYP2D6 and CYP3A. Br J Clin Pharmacol 41: pp. 181-6 CrossRef
- Callaghan, J.T., Cerimele, B.J., Kassahun, K.J. (1997) Olanzapine: interaction study with imipramine. J Clin Pharmacol 37: pp. 971-8
- Maya, J.F., Callaghan, J.T., Bergstrom, R.F. (1997) Olanzapine and warfarin drug interaction [abstract]. Clin Pharmacol Ther 61: pp. 182
- Macias, W.L., Bergstrom, R.F., Cerimele, B.J. (1998) Lack of an effect of olanzapine on the pharmacokinetics of a single aminophylline dose in healthy men. Pharmacotherapy 18: pp. 1237-48
- Demmole, D., Onkelinx, C., Muller-Oerlinghausen, B. (1995) Interaction between olanzapine and lithium in healthy male volunteers [abstract]. Therapie 50: pp. 486
- Gossen D, de Suray J-M, Vandenhende F, et al. Influence of fluoxetine on olanzapine pharmacokinetics. Indianapolis: Eli Lilly and Co., 1998. (Data on file).
- Brosen, K., Skjelbo, E., Rasmussen, B.B. (1993) Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 45: pp. 1211-4 CrossRef
- Rasmussen, B.B., Maenpaa, J., Pelkonen, O. (1995) Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine. Br J Clin Pharmacol 39: pp. 151-9 CrossRef
- Mäenpää, J., Wrighton, S., Bergstrom, R. (1997) Pharmacokinetic and pharmacodynamic interactions between fluvoxamine and olanzapine [abstract]. Clin Pharmacol Ther 61: pp. 225
- Moreland, T.A., Park, B.K., Rylance, G.W. (1982) Microsomal enzyme induction in children: the influence of carbamazepine treatment on antipyrine kinetics, 6-beta-hydroxycortisol excretion and plasma gamma-glutamyltransferase activity. Br J Clin Pharmacol 14: pp. 861-5 CrossRef
- Patsalos, P.N., Duncan, J.S. (1993) Antiepileptic drugs: areview of clinically significant drug interactions. Drug Saf 9: pp. 156-84 CrossRef
- Choonara, I., Parker, A.C., Preston, T. (1998) Induction of CYP1A2 activity by carbamazepine in children using the caffeine breath test. Br J Clin Pharmacol 45: pp. 176-8
- Lucas, R.A., Gilfillan, D.J., Bergstrom, R.F. (1998) A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanisms. Eur J Clin Pharmacol 54: pp. 639-43 CrossRef
- Boobis, A.R., Davies, D.S. (1984) Human cytochromes P-450. Xenobiotica 14: pp. 151-85 CrossRef
- Kalow, W., Tang, B.K. (1991) Caffeine as a metabolite probe: exploration of the enzyme-inducing effect of cigarette smoking. Clin Pharmacol Ther 49: pp. 44-8 CrossRef
- Sesardic, D., Boobis, A.R., Edwards, R.J. (1988) A form of cytochrome P450 in man, orthologous to form d in the rat, catalyses the O-deethylation of phenacetin and is inducible by cigarette smoking. Br J Clin Pharmacol 26: pp. 363-72 CrossRef
- Callaghan JT, Bergstrom RF, Cerimele BJ, et al. Olanzapine: bioavailability with cimetidine, antacid and charcoal. Lilly Laboratory for Clinical Research. Eli Lilly and Co. (Data on file).
- Oliver S, Wesnes K, Beuzen J-N. Olanzapine healthy elderly cognition and psychomotor study. Indianapolis: Eli Lilly and Co., 1994 (Data on file).
- Pilowsky, L.S., Busatto, G.F., Taylor, M. (1996) Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine: a 123I-IBZM single photon emission tomography (SPET) study. Psychopharmacology 124: pp. 148-53 CrossRef
- Nyberg, S., Farde, L., Halldin, C. (1997) A PET study of 5-HT2 and D2 dopamine receptor occupancy induced by olanzapine in healthy subjects. Neuropsychopharmacology 16: pp. 1-7 CrossRef
- Nordstrom, A.-L., Farde, L., Halldin, C. (1993) High 5-HT2 receptor occupancy in clozapine treated patients demonstrated by PET. Psychopharmacology 110: pp. 365-7 CrossRef
- Nordstrom, A.-L., Farde, L., Nyberg, S. (1995) D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. Am J Psychiatry 152: pp. 1444-9
- Crawford, A.M., Beasley, C.M., Tollefson, G.D. (1997) The acute and long-term effect of olanzapine compared with placebo and haloperidol on serum prolactin concentrations. Schizophrenia Res 26: pp. 41-54 CrossRef
- Tran, P.V., Hamilton, S.H., Kuntz, A.J. (1997) Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 17: pp. 407-18 CrossRef
- Tollefson, G.D., Beasley, C.M., Tran, P.V. (1997) Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 154: pp. 457-65
- Beasley, C.M., Tollefson, G., Tran, P. (1996) Olanzapine versusplacebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology 14: pp. 111-23 CrossRef
- Hamilton, S.H., Revicki, D.A., Genduso, L.A. (1998) Olanzapine versus placebo and haloperidol: quality of life and efficacy results of the North American double-blind trial. Neuropsychopharmacology 18: pp. 41-9 CrossRef
- Martin, J., Gomez, J.C., Garcia-Bernardo, E. (1997) Olanzapine in treatment-refractory schizophrenia: results of an open-label study. J Clin Psychiatry 58: pp. 479-83 CrossRef
- Beasley, C.M., Sanger, T., Satterlee, W. (1996) Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacology 124: pp. 159-67 CrossRef
- Diagnostic and statistical manual of mental disorders. APA Press, Washington, DC
- HGAD Study Team. Olanzapine (LY170053) versus placebo and haloperidol in the treatment of schizophrenia. Indianapolis: Eli Lilly and Co., 1995. (Data on file).
- Simpson, G.M., Angus, J.W. (1970) A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 212: pp. 11-9 CrossRef
- Barnes, T.R. (1989) A rating scale for drug-induced akathesia. Br J Psychiatry 154: pp. 672-6 CrossRef
- HGAD Study Team. Foxrd-dose olanzapine versus placebo in the treatment of schizophrenia. Indianapolis: Eli Lilly and Co., 1995. (Data on file).
Volume 37, Issue 3 , pp 177-193
- Cover Date
- Print ISSN
- Online ISSN
- Springer International Publishing
- Additional Links
- Industry Sectors
- Author Affiliations
- 1. Lilly Laboratory for Clinical Research, Indiana University Hospital and Outpatient Center, 550 North University Boulevard, Indianapolis, Indiana, 46202-5250, USA
- 2. Departments of Medicine and Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- 3. Department of Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- 4. Trilogy Consulting Corporation, Waukeganm, Illinois, USA
- 5. Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana, USA