European Journal of Clinical Pharmacology

, Volume 59, Issue 8–9, pp 631–636

A replicate study design for testing bioequivalence: a case study on two desmopressin nasal spray preparations

  • Christian Joukhadar
  • Barbara Schenk
  • Stefan T. Kaehler
  • Christian J. Kollenz
  • Peter Bauer
  • Markus Müller
  • Hans-Georg Eichler
Pharmacokinetics and Disposition

Abstract

Objective

The present study was carried out to test bioequivalence between two different desmopressin nasal spray preparations. Due to the high variability of plasma pharmacokinetics of intranasally administered peptides like desmopressin, appropriate study designs are required to assess bioequivalence. Therefore, a single-dose, replicate study design was used to evaluate bioequivalence of two desmopressin nasal sprays.

Subjects and methods

Thirty-two healthy male volunteers were enrolled in the study and were randomly assigned to receive the test- and reference drug on two occasions in a 4-period 2-sequence crossover study design. Subjects received a single dose of 20 µg (10 µg per nostril) of desmopressin-acetate per study day separated by wash-out periods of at least 1 week. Desmopressin blood concentrations were measured serially over a 14-h period using a validated radioimmunoassay method. Statistical analysis was initially performed using a complicated mixed-analysis model testing for individual bioequivalence according to recommendations by the Food and Drug Administration. This approach, however, failed to converge with all defined main PK parameters and, thus, a traditional mixed analysis of variance analysis based on population averages was definitely used for testing bioequivalence between study drugs. The procedure of selecting an appropriate statistical analysis for a replicate study design was predefined in the study protocol.

Results

The 90% confidence intervals (CI) were calculated for the area under the time–concentration curve (AUC), maximum concentration (Cmax) and the time to reach Cmax (tmax) of test/reference drug ratios for a bioequivalence range from 0.80–1.25. The mean test/reference drug ratios were completely within the 90% CIs with values of 1.041 (CI: 0.892–1.216), 1.021 (CI: 0.913–1.140) and 1.068 (CI: 0.914–1.249) for AUC0–14 h, Cmax and tmax, respectively.

Conclusion

The rate and the extent of intranasal desmopressin absorption are identical for both study preparations. Thus, the desmopressin test preparation met all equivalence criteria and thereby was proven bioequivalent with a marketed reference nasal desmopressin spray.

Keywords

Desmopressin 4-Period 2-sequence crossover study Human 

References

  1. 1.
    Andersson KE, Arner B (1972) Effects of DDAVP, a synthetic analogue of vasopressin, in patients with cranial diabetes insipidus. Acta Med Scand 192:21–27PubMedGoogle Scholar
  2. 2.
    Becker DJ, Foley TP, Jr (1978) 1-Deamino-8-d-arginine vasopressin in the treatment of central diabetes insipidus in childhood. J Pediatr 92:1011–1015PubMedGoogle Scholar
  3. 3.
    Dimson SB (1977) Desmopressin as a treatment for enuresis. Lancet 1:1260CrossRefGoogle Scholar
  4. 4.
    Pedersen PS, Hejl M, Kjoller SS (1985) Desamino-d-arginine vasopressin in childhood nocturnal enuresis. J Urol 133:65–66PubMedGoogle Scholar
  5. 5.
    Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A (1977) D.D.A.V.P. in haemophilia. Lancet 2:1171–1172PubMedGoogle Scholar
  6. 6.
    Vilhardt H, Aberg M, Nilsson IM (1980) Possible use of DDAVP in coagulation disorders. In: Sutor AH, Schattauer FK (eds) DDAVP in bleeding disorders. Schattauer, Stuttgart, pp 36–41Google Scholar
  7. 7.
    Fjellestad-Paulsen A, Hoglund P, Lundin S, Paulsen O (1993) Pharmacokinetics of 1-deamino-8-D-arginine vasopressin after various routes of administration in healthy volunteers. Clin Endocrinol (Oxf) 38:177–182Google Scholar
  8. 8.
    Eller N, Kollenz CJ, Bauer P, Hitzenberger G (1998) The duration of antidiuretic response of two desmopressin nasal sprays. Int J Clin Pharmacol Ther 36:494–500PubMedGoogle Scholar
  9. 9.
    Eller N, Kollenz CJ, Hitzenberger G (1998) A comparative study of pharmacodynamics and bioavailability of 2 different desmopressin nasal sprays. Int J Clin Pharmacol Ther 36:139–145PubMedGoogle Scholar
  10. 10.
    O’Doherty DP, Bickerstaff DR, McCloskey EV, Atkins R, Hamdy NA, Kanis JA (1990) A comparison of the acute effects of subcutaneous and intranasal calcitonin. Clin Sci (Lond) 78:215–219Google Scholar
  11. 11.
    Fiore CE, Romagnoli A, Foti R, Coppini A (1991) Assessment of the biological activity of synthetic salmon calcitonin by intranasal administration in healthy volunteers. Drugs Exp Clin Res 17:537–542PubMedGoogle Scholar
  12. 12.
    Combe B, Cohen C, Aubin F (1997) Equivalence of nasal spray and subcutaneous formulations of salmon calcitonin. Calcif Tissue Int 61:10–15CrossRefPubMedGoogle Scholar
  13. 13.
    Christians U, First MR, Benet LZ (2000) Recommendations for bioequivalence testing of cyclosporine generics revisited. Ther Drug Monit 22:330–345CrossRefPubMedGoogle Scholar
  14. 14.
    Lundin S, Vilhardt H (1986) Absorption of 1-deamino-8-d-arginine vasopressin from different regions of the gastrointestinal tract in rabbits. Acta Endocrinol (Copenh) 112:457–460Google Scholar
  15. 15.
    Food and Drug Administration, Center for Drug Evaluation and Research, 1998b: Statistical methods for obtaining confidence intervals for individual and population bioequivalence criteria.http://www.fda.gov/cder/bioequivdata/statproc.htm
  16. 16.
    Guidance for Industry—bioavailability and bioequivalence studies for orally administered drug products—general considerations.http://www.fda.gov/cder/guidance/3615fnl.pdf, FDA/CDER (Oct 2001)
  17. 17.
    Note for guidance on the investigation of bioavailability and bioequivalence, CPMP/EWP/QWP/1401/98, EMEA (2001)Google Scholar
  18. 18.
    Chen ML, Lesko LJ (2001) Individual bioequivalence revisited. Clin Pharmacokinet 40:701–706PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Christian Joukhadar
    • 1
    • 2
  • Barbara Schenk
    • 1
  • Stefan T. Kaehler
    • 3
  • Christian J. Kollenz
    • 3
  • Peter Bauer
    • 4
  • Markus Müller
    • 1
  • Hans-Georg Eichler
    • 1
  1. 1.Department of Clinical Pharmacology, Division of Clinical PharmacokineticsUniversity of Vienna Medical School, Allgemeines KrankenhausViennaAustria
  2. 2.Institute of PharmacologyUniversity of ViennaAustria
  3. 3.Medical DepartmentGebro Pharma GmbHFieberbrunnAustria
  4. 4.Institute of Medical Statistics and DocumentationUniversity of ViennaAustria

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