Clinical Pharmacokinetics

, Volume 37, Issue 3, pp 177–193 | Cite as

Olanzapine

Pharmacokinetic and Pharmacodynamic Profile
  • John T. Callaghan
  • Richard F. Bergstrom
  • Louis R. Ptak
  • Charles M. Beasley
Review Articles Drug Disposition

Abstract

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.

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References

  1. 1.
    Moore NA, Calligaro DO, Wong DT, et al. The pharmacology of olanzapine, and other new antipsychotic agents. Curr Opin Invest Drugs 1993; 2: 281–93.Google Scholar
  2. 2.
    Casey DE. What makes a neuroleptic atypical? In: Meltzer HY, editor. Novel antipsychotic drugs. New York: Raven, 1992: 241–51.Google Scholar
  3. 3.
    Meltzer HY. The mechanism of action of clozapine in relation to its clinical advantages. In: Meltzer HY, editor. Novel antipsychotic drugs. New York: Raven, 1992: 1–13.Google Scholar
  4. 4.
    Fuller A, Snoddy HD. Neuroendocrine evidence for antagonism of serotonin and dopamine receptors by olanzapine (LY170053) an antipsychotic drug candidate. Res Commun Chem Pathol Pharmacol 1992; 77 (1): 87–93.PubMedGoogle Scholar
  5. 5.
    Bymaster FP, Calligaro DO, Falcone JF, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 1996; 14 (2): 87–96.PubMedCrossRefGoogle Scholar
  6. 6.
    Corbett R, Camacho F, Woods AT, et al. Antipsychotic agents antagonize non-competitive N-methyl-D-aspartate antagonist-induced behaviors. Psychopharmacology (Berl) 1995; 120: 67–74.CrossRefGoogle Scholar
  7. 7.
    Beasley CM. Efficacy of olanzapine: an overview of pivotal clinical trials. J Clin Psychiatry Monogr 1997; 15: 16–8.Google Scholar
  8. 8.
    Tollefson GD, Beasley CM, Tamura RN, et al. Blind, controlled, long-term study of the comparative incidence of treatment-emergenttardive dyskinesia with olanzapine or haloperidol. Am J Psychiatry 1997; 154 (9): 1248–54.PubMedGoogle Scholar
  9. 9.
    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).Google Scholar
  10. 10.
    Bergstrom RF, Callaghan JT, Cerimele BJ, et al. Pharmacokinetics of olanzapine in elderly and young. Pharm Res 1995; 12 Suppl. 9: S–358.Google Scholar
  11. 11.
    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).Google Scholar
  12. 12.
    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).Google Scholar
  13. 13.
    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).Google Scholar
  14. 14.
    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).Google Scholar
  15. 15.
    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).Google Scholar
  16. 16.
    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).Google Scholar
  17. 17.
    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).Google Scholar
  18. 18.
    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).Google Scholar
  19. 19.
    Kassahun K, Mattiuz E, Nyhart Jr E, et al. Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drug Metab Dispos 1997; 25 (1): 81–93.PubMedGoogle Scholar
  20. 20.
    Ring BJ, Catlow J, Lindsay TJ, et al. 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: 658–66.PubMedGoogle Scholar
  21. 21.
    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).Google Scholar
  22. 22.
    Patel BR, Kurtz DL. Population pharmacokinetic analyses of olanzapine. Indianapolis: Eli Lilly and Co., 1995 (Data on file).Google Scholar
  23. 23.
    Ring BJ, Binkley SN, Vandenbranden M, et al. In vitro interaction of the antipsychotic agent olanzapine with human cytochromes P450 CYP2C9, CYP2C19, CYP2D6 and CYP3A. Br J Clin Pharmacol 1996; 41: 181–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Callaghan JT, Cerimele BJ, Kassahun KJ, et al. Olanzapine: interaction study with imipramine. J Clin Pharmacol 1997; 37 (10): 971–8.PubMedGoogle Scholar
  25. 25.
    Maya JF, Callaghan JT, Bergstrom RF, et al. Olanzapine and warfarin drug interaction [abstract]. Clin Pharmacol Ther 1997; 61 (2): 182.Google Scholar
  26. 26.
    Macias WL, Bergstrom RF, Cerimele BJ, et al. Lack of an effect of olanzapine on the pharmacokinetics of a single aminophylline dose in healthy men. Pharmacotherapy 1998; 18 (6): 1237–48.PubMedGoogle Scholar
  27. 27.
    Demmole D, Onkelinx C, Muller-Oerlinghausen B. Interaction between olanzapine and lithium in healthy male volunteers [abstract]. Therapie 1995; 50 Suppl.: 486.Google Scholar
  28. 28.
    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).Google Scholar
  29. 29.
    Brosen K, Skjelbo E, Rasmussen BB, et al. Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 1993; 45 (6): 1211–4.PubMedCrossRefGoogle Scholar
  30. 30.
    Rasmussen BB, Maenpaa J, Pelkonen O, et al. Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine. Br J Clin Pharmacol 1995; 39 (2): 151–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Mäenpää J, Wrighton S, Bergstrom R, et al. Pharmacokinetic and pharmacodynamic interactions between fluvoxamine and olanzapine [abstract]. Clin Pharmacol Ther 1997; 61 (2): 225.Google Scholar
  32. 32.
    Moreland TA, Park BK, Rylance GW. 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 1982; 14 (6): 861–5.PubMedCrossRefGoogle Scholar
  33. 33.
    Patsalos PN, Duncan JS. Antiepileptic drugs: areview of clinically significant drug interactions. Drug Saf 1993; 9 (3): 156–84.PubMedCrossRefGoogle Scholar
  34. 34.
    Choonara I, Parker AC, Preston T, et al. Induction of CYP1A2 activity by carbamazepine in children using the caffeine breath test. Br J Clin Pharmacol 1998; 45 (2): 176–8.PubMedGoogle Scholar
  35. 35.
    Lucas RA, Gilfillan DJ, Bergstrom RF. A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanisms. Eur J Clin Pharmacol 1998 Oct; 54 (8): 639–43.PubMedCrossRefGoogle Scholar
  36. 36.
    Boobis AR, Davies DS. Human cytochromes P-450. Xenobiotica 1984; 14 (1–2): 151–85.PubMedCrossRefGoogle Scholar
  37. 37.
    Kalow W, Tang BK. Caffeine as a metabolite probe: exploration of the enzyme-inducing effect of cigarette smoking. Clin Pharmacol Ther 1991; 49 (1): 44–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Sesardic D, Boobis AR, Edwards RJ, et al. 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 1988; 26 (4): 363–72.PubMedCrossRefGoogle Scholar
  39. 39.
    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).Google Scholar
  40. 40.
    Oliver S, Wesnes K, Beuzen J-N. Olanzapine healthy elderly cognition and psychomotor study. Indianapolis: Eli Lilly and Co., 1994 (Data on file).Google Scholar
  41. 41.
    Pilowsky LS, Busatto GF, Taylor M, et al. Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine: a 123I-IBZM single photon emission tomography (SPET) study. Psychopharmacology 1996; 124: 148–53.PubMedCrossRefGoogle Scholar
  42. 42.
    Nyberg S, Farde L, Halldin C. A PET study of 5-HT2 and D2 dopamine receptor occupancy induced by olanzapine in healthy subjects. Neuropsychopharmacology 1997; 16 (1): 1–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Nordstrom A-L, Farde L, Halldin C. High 5-HT2 receptor occupancy in clozapine treated patients demonstrated by PET. Psychopharmacology 1993; 110: 365–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Nordstrom A-L, Farde L, Nyberg S, et al. D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. Am J Psychiatry 1995; 152 (10): 1444–9.PubMedGoogle Scholar
  45. 45.
    Crawford AM, Beasley CM, Tollefson GD. The acute and long-term effect of olanzapine compared with placebo and haloperidol on serum prolactin concentrations. Schizophrenia Res 1997; 26: 41–54.CrossRefGoogle Scholar
  46. 46.
    Tran PV, Hamilton SH, Kuntz AJ, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997; 17 (5): 407–18.PubMedCrossRefGoogle Scholar
  47. 47.
    Tollefson GD, Beasley CM, Tran PV, et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 1997; 154 (4): 457–65.PubMedGoogle Scholar
  48. 48.
    Beasley CM, Tollefson G, Tran P, et al. Olanzapine versusplacebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology 1996; 14 (2): 111–23.PubMedCrossRefGoogle Scholar
  49. 49.
    Hamilton SH, Revicki DA, Genduso LA, et al. Olanzapine versus placebo and haloperidol: quality of life and efficacy results of the North American double-blind trial. Neuropsychopharmacology 1998; 18 (1): 41–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Martin J, Gomez JC, Garcia-Bernardo E, et al. Olanzapine in treatment-refractory schizophrenia: results of an open-label study. J Clin Psychiatry 1997; 58 (11): 479–83.PubMedCrossRefGoogle Scholar
  51. 51.
    Beasley Jr CM, Sanger T, Satterlee W, et al. Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacology 1996; 124: 159–67.PubMedCrossRefGoogle Scholar
  52. 52.
    American Psychiatric Association Task Force on Nomenclature and Statistics. Diagnostic and statistical manual of mental disorders. 3rd rev ed. Washington, DC: APA Press, 1987.Google Scholar
  53. 53.
    HGAD Study Team. Olanzapine (LY170053) versus placebo and haloperidol in the treatment of schizophrenia. Indianapolis: Eli Lilly and Co., 1995. (Data on file).Google Scholar
  54. 54.
    Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 1970; 212 Suppl.: 11–9.CrossRefGoogle Scholar
  55. 55.
    Barnes TR. A rating scale for drug-induced akathesia. Br J Psychiatry 1989; 154: 672–6.PubMedCrossRefGoogle Scholar
  56. 56.
    HGAD Study Team. Foxrd-dose olanzapine versus placebo in the treatment of schizophrenia. Indianapolis: Eli Lilly and Co., 1995. (Data on file).Google Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  • John T. Callaghan
    • 1
    • 2
  • Richard F. Bergstrom
    • 1
    • 3
  • Louis R. Ptak
    • 1
    • 4
  • Charles M. Beasley
    • 1
    • 5
  1. 1.Lilly Laboratory for Clinical ResearchIndiana University Hospital and Outpatient CenterIndianapolisUSA
  2. 2.Departments of Medicine and PharmacologyIndiana University School of MedicineIndianapolisUSA
  3. 3.Department of PharmacologyIndiana University School of MedicineIndianapolisUSA
  4. 4.Trilogy Consulting CorporationWaukeganmUSA
  5. 5.Eli Lilly and Company, Lilly Research LaboratoriesLilly Corporate CenterIndianapolisUSA

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