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


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 microg (10 microg 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 (C(max)) and the time to reach C(max) (t(max)) 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 AUC(0-14 h), C(max) and t(max), respectively.


CONCLUSIONS
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.
Joukhadar
Christian
C
Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, University of Vienna Medical School, Allgemeines Krankenhaus, Waehringer Guertel 18-20, 1090 Vienna, Austria. christian.joukhadar@univie.ac.at
Schenk
Barbara
B
Kaehler
Stefan T
ST
Kollenz
Christian J
CJ
Bauer
Peter
P
Müller
Markus
M
Eichler
Hans-Georg
HG
D000281:Administration, Intranasal; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D003627:Data Interpretation, Statistical; D003894:Deamino Arginine Vasopressin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D012076:Renal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D013810:Therapeutic Equivalency
D012076:Renal Agents; D003894:Deamino Arginine Vasopressin