Clinical Drug Investigation

, Volume 17, Issue 1, pp 51–58 | Cite as

A Bioequivalence Study of Brand and Generic Clozapine in Patients with Schizophrenia

Pharmacokinetic and Tolerability Findings
  • John J. Sramek
  • Ravi Anand
  • Richard D. Hartman
  • Horst F. Schran
  • Jameel Hourani
  • Sharon Barto
  • Tom S. Wardle
  • Thomas M. Shiovitz
  • Neal R. Cutler
Clinical Pharmacokinetics

Abstract

Objective: This inpatient, randomised, three-way crossover study evaluated the steady-state pharmacokinetics and tolerability of generic clozapine (Creighton) versus Clozaril® (Novartis brand of clozapine) in patients with schizophrenia.

Setting: Patients were hospitalised throughout the study.

Patients: Thirty patients meeting DSM-III-R criteria for a diagnosis of schizophrenia participated in this study.

Design: Clozaril® was titrated over 5 days from 12.5 to 75mg twice daily, after which patients received all of the following 1-week regimens in random order: Clozaril® — one 100mg tablet twice daily; clozapine — four 25mg tablets twice daily; and clozapine — one 100mg tablet twice daily.

Main Outcome Measures and Results: Both the 25 and 100mg dose forms of clozapine were bioequivalent to Clozaril® 100mg, justifying their interchange-ability; mean area under the concentration-time curve (AUC0–12) values were 2683 ± 1613, 2781 ± 1775, and 2547 ± 1429 μg/L·h, respectively. The most common adverse events were dizziness and asthenia. Tolerability findings between groups were comparable, although a high incidence (20%) of symptomatic orthostatic hypotension during the initial titration of Clozaril® emphasised the need for careful monitoring, even in the target patient population.

Conclusions: The results of this study demonstrated that the 25 and 100mg dose forms of generic clozapine and Clozaril® 100mg are bioequivalent, which should ensure comparable efficacy and tolerability with the clinical use of either product.

Keywords

Schizophrenia Adis International Limited Clozapine Schizophrenic Patient Bioequivalence Study 

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References

  1. 1.
    Kane JM, Schooler NR, Marder SR, et al. Methods for clinical evaluation of pharmacologic treatments of schizophrenia. In: Prien RF, Robinson DS, editors. Clinical evaluation of psychotropic drugs. New York: Raven Press, 1994: 345–72Google Scholar
  2. 2.
    Jann MW. Clozapine. Pharmacotherapy 1991; 11(3): 179–95PubMedGoogle Scholar
  3. 3.
    Perry PJ, Miller DD, Arndt SV, et al. Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry 1991; 148(2): 231–5PubMedGoogle Scholar
  4. 4.
    Ereshefsky L, Watanabe MD, Tran-Johnson TK. Clozapine: an atypical antipsychotic agent. Clin Pharm 1989; 8: 691–709PubMedGoogle Scholar
  5. 5.
    Ackenheil M. Clozapine — pharmacokinetic investigations and biochemical effects in man. Psychopharmacology (Berlin) 1989; 99 Suppl.: S32–S37CrossRefGoogle Scholar
  6. 6.
    Haring C, Meise U, Humpel C, et al. Dose-related plasma levels of clozapine: influence of smoking behavior, sex, and age. Psychopharmacology (Berlin) 1989; 99 Suppl.: S38–S40CrossRefGoogle Scholar
  7. 7.
    Taylor D. Pharmacokinetic interactions involving clozapine. Br J Psychiatry 1997; 171: 109–12PubMedCrossRefGoogle Scholar
  8. 8.
    Bertilsson L, Carrillo JA, Dahl ML, et al. Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. Br J Clin Pharmacol 1994; 38(5): 471–3PubMedCrossRefGoogle Scholar
  9. 9.
    Kuoppamaki M, Syvalahti E, Hietala J. Clozapine and N-desmethylclozapine are potent 5-HT1c receptor antagonists. Eur J Pharmacol 1996; 245(2): 179–82Google Scholar
  10. 10.
    Potkin SG, Bera R, Gulasekaram B, et al. Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia. J Clin Psychiatry 1994; 55 Suppl. B: 133–6PubMedGoogle Scholar
  11. 11.
    VanderZwaag C, McGee M, McEvoy JP, et al. Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges. Am J Psychiatry 1996; 153(12): 1579–84PubMedGoogle Scholar
  12. 12.
    Miller AL, Maas JW, Contreras S, et al. Acute effects of neuroleptics on unmedicated schizophrenic patients and controls. Biol Psychiatry 1993; 34: 178–87PubMedCrossRefGoogle Scholar
  13. 13.
    Gelijns AC. Modern methods of clinical investigation. Washington, DC: National Academy Press, 1990Google Scholar
  14. 14.
    Pokorny R, Finkel MJ, Robinson WT. Normal volunteers should not be used for bioavailability or bioequivalence studies of clozapine. Pharm Res 1994; 11(8): 1221PubMedCrossRefGoogle Scholar
  15. 15.
    Food and Drug Administration. FDA update on clozapine guidelines. Rockville, MD, 1996Google Scholar
  16. 16.
    American Psychiatric Association, editor. Diagnostic and statistical manual of mental disorders. 3rd ed revised. Washington, DC: American Psychiatric Press, 1987Google Scholar
  17. 17.
    Kay SR, Fizbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–76PubMedGoogle Scholar
  18. 18.
    Choc MG, Lehr RG, Hsuan F, et al. Multiple-dose pharmacokinetics of clozapine in patients. Pharm Res 1987; 4(5): 402–5PubMedCrossRefGoogle Scholar
  19. 19.
    Physician’s Desk Reference. 51st ed. Montvale: Medical Economics Company, 1997: 2377Google Scholar
  20. 20.
    Choc MG, Hsuan F, Honigfeld G, et al. Single- vs. multiple-dose pharmacokinetics of clozapine in psychiatric patients. Pharm Res 1990; 7(4): 347–51PubMedCrossRefGoogle Scholar
  21. 21.
    Cheng YF, Lundberg T, Bondesson U, et al. Clinical pharmacokinetics of clozapine in chronic schizophrenia patients. Eur J Clin Pharmacol 1988; 34(5): 445–9PubMedCrossRefGoogle Scholar
  22. 22.
    Carpenter Jr WT, Conley RR, Buchanan RW, et al. Patient response and resource management: another view of clozapine treatment of schizophrenia. Am J Psychiatry 1995; 152(6): 827–32PubMedGoogle Scholar
  23. 23.
    Ranjan R, Meltzer HY. Acute and long-term effectiveness of clozapine in treatment-resistant psychotic depression. Biol Psychiatry 1996; 40(4): 253–8PubMedCrossRefGoogle Scholar
  24. 24.
    Calabrese JR, Kimmel SE, Woyshville MJ, et al. Clozapine for treatment-refractory mania. Am J Psychiatry 1996; 153(6): 759–64PubMedGoogle Scholar
  25. 25.
    Oberholzer AF, Hendriksen C, Monsch AU, et al. Safety and effectiveness of low-dose clozapine in psychogeriatric patients: a preliminary study. Int Psychogeriatr 1992; 4(2): 187–95PubMedCrossRefGoogle Scholar
  26. 26.
    Chacko RC, Hurley RA, Harper RG, et al. Clozapine for acute and maintenance treatment of psychosis in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1995; 7(4): 471–5PubMedGoogle Scholar
  27. 27.
    Safferman AZ, Kane JM, Aronowitz JS, et al. The use of clozapine in neurologic disorders. J Clin Psychiatry 1994; 55 Suppl. B: 98–101PubMedGoogle Scholar
  28. 28.
    Sramek JJ, Fresquet A, Marion-Landais G, et al. Establishing the maximum tolerated dose of lesopitron in patients with generalized anxiety disorder: a bridging study. J Clin Psychopharmacol 1996; 16(6): 454–8PubMedCrossRefGoogle Scholar
  29. 29.
    Grof P, Akhter MI, Campbell M, et al. Clinical evaluation of psychotropic drugs for psychiatric disorders: principles and proposed guidelines. Seattle: Hogrefe & Huber, 1993Google Scholar
  30. 30.
    Sramek JJ, Hurley DJ, Wardle TS, et al. The safety and tolerance of xanomeline tartrate in patients with Alzheimer’s disease. J Clin Pharmacol 1995; 35(8): 800–6PubMedGoogle Scholar
  31. 31.
    Goldberg MR, Barchowsky A, McCrea J, et al. Heptylphysostigmine (L-693,487): safety and cholinesterase inhibition in a placebo-controlled rising-dose healthy volunteers study [abstract]. Second International Springfield Symposium on Advances in Alzheimer Therapy; 1991 May. Springfield, IL, USAGoogle Scholar
  32. 32.
    Sramek JJ, Sedman AF, Reece PA, et al. Safety and tolerability of CI-979 in patients with Alzheimer’s disease. Life Sci 1995; 57(5): 503–10PubMedCrossRefGoogle Scholar
  33. 33.
    Cutler NR, Sramek JJ. Scientific and ethical concerns in clinical trials in Alzheimer’s patients: the bridging study. Eur J Clin Pharmacol 1995; 48(6): 421–8PubMedCrossRefGoogle Scholar
  34. 34.
    Cutler NR, Sramek JJ. The target population in phase I clinical trials of cholinergic compounds in Alzheimer’s disease: the role of the ‘bridging study.’ Alzheimer Dis Assoc Disord 1995; 9: 139–45Google Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  • John J. Sramek
    • 1
  • Ravi Anand
    • 2
  • Richard D. Hartman
    • 2
  • Horst F. Schran
    • 2
  • Jameel Hourani
    • 1
  • Sharon Barto
    • 1
  • Tom S. Wardle
    • 1
  • Thomas M. Shiovitz
    • 1
  • Neal R. Cutler
    • 1
  1. 1.California Clinical TrialsBeverly HillsUSA
  2. 2.Novartis Pharmaceuticals CorporationEast HanoverUSA

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