Drug Res (Stuttg) 2013; 63(07): 346-350
DOI: 10.1055/s-0033-1341427
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Single Dose Bioequivalence Study of Two Brands of Olanzapine 10 mg Tablets in Iranian Healthy Volunteers

P. Zakeri-Milani
1   Liver and Gastrointestinal Diseases Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
Z. Islambulchilar
2   Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
3   Faculty of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
S. Ghanbarzadeh
4   Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
H. Valizadeh
5   Research Center for Pharmaceutical Nanotechnology and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
› Institutsangaben
Weitere Informationen


received 24. Oktober 2012

accepted 27. Februar 2013

19. April 2013 (online)


This single dose, randomized, open label, 2-period and crossover study in healthy Iranian adult volunteers was conducted to compare the bioavailability of 2 branded formulations of olanzapine 10 mg tablets. 24 volunteers received one tablet of each olanzapine 10 mg formulation. Drugs were administered after a 12 h overnight fast in each of 2 treatment days which separated by a 2-week washout period. Serial blood samples were collected over a period of 72 h. Plasma was analyzed using a validated high performance liquid chromatography method with ultraviolet detection in the range of 2–24 ng/mL with a lower limit of quantitation of 1.25 ng/mL. A non-compartmental method was employed to determine the pharmacokinetic properties (Cmax, Tmax, AUC0–t, AUC0–∞ and T1/2) to test to bioequivalence. Cmax, AUC0–t and AUC0–∞ were used to test the bioequivalence after log-transformation of plasma data. The mean (SD) Cmax, AUC0–t and AUC0–∞ for the test formulation were 15.82 (3.15) ng/mL, 447.19 (100.64) ng.h/L and 570.75 (130.55) ng.h/L respectively. Corresponding values for the test formulation were 15.72 (4.25) ng/mL, 440.37 (98.75) ng.h/mL and 558.66 (129.57) ng.h/mL. For test formulation vs. the reference formulation, the 90% CIs of the least squares mean test/reference ratios of Cmax, AUC0–t and AUC0–∞ were 97.6–110.0%, 96.4–109.4% and 97.3–109.2%. In these volunteers, based on the FDA regulatory definition, results from the pharmacokinetic analysis suggested that the test and reference formulations of olanzapine 10 mg tablets were bioequivalent.

  • References

  • 1 Bitter I, Dossenbach MRK, Brook S et al. Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 173-180
  • 2 Breier A, Hamilton SH. Comparative efficacy of olanzapine and haloperidol for patients with treatment-resistant schizophrenia. Biol Psychiatry 1999; 45: 403-411
  • 3 Ciudad A, Gutarrez M, Caeas F et al. Safety and effectiveness of olanzapine in monotherapy: A multivariate analysis of a naturalistic study. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 944-951
  • 4 Kontaxakis VP, Havaki-Kontaxaki BJ, Christodoulou NG et al. Olanzapine-associated neuroleptic malignant syndrome. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 897-902
  • 5 Maciulis V, Bitter I, Milasiunas R et al. Efficacy and tolerability of olanzapine in patients with schizophrenia in lithuania: A 13-week, multicenter, open-label, nonrandomized study. Cur Ther Res 2004; 65: 57-69
  • 6 Marx CE, Shampine LJ, Khisti RT et al. Olanzapine and fluoxetine administration and coadministration increase rat hippocampal pregnenolone, allopregnanolone and peripheral deoxycorticosterone: Implications for therapeutic actions. Pharmacol Biochem Behav 2006; 84: 609-617
  • 7 Shafti SS. Olanzapine vs. lithium in management of acute mania. J Affect Disord 2001; 122: 273-276
  • 8 Boulton DW, Markowitz JS, DeVane CL. A high-performance liquid chromatography assay with ultraviolet detection for olanzapine in human plasma and urine. J Chromatogr B Biomed Sci Appl 2001; 759: 319-323
  • 9 Dossenbach MRK, Folnegovic-Smalc V, Uglesic B et al. Double-blind, randomized comparison of olanzapine versus fluphenazine in the long-term treatment of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 311-318
  • 10 Jasiaska A, Nalewajko E. Batch and flow-injection methods for the spectrophotometric determination of olanzapine. Anal Chim Acta 2004; 508: 165-170
  • 11 Saeed B, Valizadeh H, Zakeri-Milani P. Comparative in vitro dissolution and in vivo bioequivalence of two diclofenac enteric coated formulations. Arzneimittelforschung 2011; 61: 566-570
  • 12 Dusci LJ, Peter Hackett L, Fellows LM et al. Determination of olanzapine in plasma by high-performance liquid chromatography using ultraviolet absorbance detection. J Chromatogr B 2002; 773: 191-197
  • 13 Raggi M, Casamenti G, Mandrioli R et al. A sensitive high-performance liquid chromatographic method using electrochemical detection for the analysis of olanzapine and desmethylolanzapine in plasma of schizophrenic patients using a new solid-phase extraction procedure. J Chromatogr B Biomed Sci Appl 2001; 750: 137-146
  • 14 Berna M, Ackermann B, Ruterbories K et al. Determination of olanzapine in human blood by liquid chromatography tandem mass spectrometry. J Chromatogr B 2002; 767: 163-168
  • 15 Sabbioni C, Saracino MA, Mandrioli R et al. Rapid analysis of olanzapine and desmethylolanzapine in human plasma using high-performance liquid chromatography with coulometric detection. Anal Chim Acta 2004; 516: 111-117
  • 16 Saracino MA, Gandolfi O, Dall OR et al. Determination of Olanzapine in rat brain using liquid chromatography with coulometric detection and a rapid solid-phase extraction procedure. J Chromatogr A 2006; 1122: 21-27
  • 17 Zhang G, Terry Jr AV, Bartlett MG. Sensitive liquid chromatography/tandem mass spectrometry method for the simultaneous determination of olanzapine, risperidone, 9-hydroxyrisperidone, clozapine, haloperidol and ziprasidone in rat brain tissue. J Chromatogr B 2007; 858: 276-281
  • 18 Zakeri-Milani P, Barzegar-Jalali M, Tajerzadeh H et al. Simultaneous determination of naproxen, ketoprofen and phenol red in samples from rat intestinal permeability studies: HPLC method development and validation. J Pharm Biomed Anal 2005; 39: 624-630
  • 19 Zakeri-Milani P, Valizadeh H, Islambulchilar Z. Comparative bioavailability study of two cefixime formulations administered orally in healthy male volunteers. Arzneimittelforschung 2008; 58: 97-100
  • 20 Valizadeh H, Nemati M, Hallaj-Nezhadi S et al. Single dose bioequivalence study of alpha methyldopa tablet formulations using a modified HPLC method. Arzneimittelforschung 2010; 60: 607-611
  • 21 Shargel L, Wu-Pong S, Yu A. Applied biopharmaceutics and pharmacokinetics. McGraw-Hill Education 2005;
  • 22 Zou JJ, Ji HJ, Wu DW et al. Bioequivalence and pharmacokinetic comparison of a single 200-mg dose of meclofenoxate hydrochloride capsule and tablet formulations in healthy chinese adult male volunteers: a randomized sequence, open-label, two-period crossover study. Clin Ther 2008; 30: 1651-1657
  • 23 Rhim SY, Park JH, Park YS et al. Bioavailability and bioequivalence of two oral formulations of alendronate sodium 70 mg: An open-label, randomized, two-period crossover comparison in healthy Korean adult male volunteers. Clin Ther 2009; 31: 1037-1045
  • 24 Zhang Q, Tao Y, Zhu Y et al. Bioequivalence and pharmacokinetic comparison of two mycophenolate mofetil formulations in healthy Chinese male volunteers: An open-label, randomized-sequence, single-dose, two-way crossover study. Clin Ther 2010; 32: 171-178
  • 25 Guidance for Industry, Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations. Rockville, MD: U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER); 2003. [cited 2013 February]; Available from http://www.fda.gov/downloads/Drugs/…/Guidances/ucm070124.pdf
  • 26 Guideline on the investigation of bioequivalence. London, UK: European Medicines Agency; 2010. [cited 2013 February]; Available from http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf
  • 27 Erkent U, Koytchev R. The use of truncated area under the curves in the bioequivalence evaluation of long half-life drugs. Studies with donepezil and memantine. Arzneimittelforsch 2008; 58: 255-258
  • 28 Endrenyi L, Tothfalusi L. Truncated AUC evaluates effectively the bioequivalence of drugs with long half-lives. Int J Clin Pharmacol Ther 1997; 35: 142-150
  • 29 Guidance Document – Comparative Bioavailability Standards: Formulations Used for Systemic Effects. Ottawa, Canada: Health Canada; 2012. [cited 2013 February]; Available from http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/bio/gd_standards_ld_normes-eng.php
  • 30 Elshafeey AH, Elsherbiny MA, Fathallah MM. A single-dose, randomized, two-way crossover study comparing two olanzapine tablet products in healthy adult male volunteers under fasting conditions. Clin Ther 2009; 31: 600-608
  • 31 Olesen OV, Linnet K. Determination of olanzapine in serum by high-performance liquid chromatography using ultraviolet detection considering the easy oxidability of the compound and the presence of other psychotropic drugs. J Chromatogr B Biomed Sci Appl 1998; 714: 309-315
  • 32 Kasper SC, Mattiuz EL, Swanson SP et al. Determination of olanzapine in human breast milk by high-performance liquid chromatography with electrochemical detection. J Chromatogr B Biomed Sci Appl 1999; 726: 203-209
  • 33 Raggi MA, Casamenti G, Mandrioli R et al. Quantitation of olanzapine in tablets by HPLC, CZE, derivative spectrometry and linear voltammetry. J Pharm Biomed Anal 2000; 23: 973-981