title: Implications of different application sites on the bioavailability of a transdermal contraceptive patch containing ethinyl estradiol and gestodene: an open-label, randomized, crossover study.
abstract: OBJECTIVE
  A novel once-a-week contraceptive patch delivers the same systemic exposure seen with a combined oral contraceptive pill containing 0.02 mg ethinyl estradiol (EE) and 0.06 mg gestodene (GSD). This study evaluated the relative bioavailability of EE and GSD after application of this patch to three different sites.
  
  
  METHODS
  In this phase I, open-label, randomized, intra-individual comparison, crossover study, 43 women (aged 18 - 45 years) were randomized to one of six treatment sequences. Patches were applied to two test sites (buttocks and outer, upper arm) and one comparator site (lower abdomen). In each treatment period, four patches were worn for 7 days each, followed by a 7-day, patch-free interval. The primary objective was to investigate the relative bioavailability of transdermally administered EE and GSD between test and comparator sites using the primary variable area under the concentration- time curve (AUC(0-168)) during week 4 of each period.
  
  
  RESULTS
  Of the 43 women who were randomized, 43 were included in the set for safety evaluation and 40 were included in the set for pharmacokinetic (PK) analysis. Three subjects were excluded from the PK analysis as they failed to complete the study. AUC(0-168) for EE and GSD were equal when the patch was applied to buttocks or abdomen (AUC(0-168) ratios: EE, 1.07 (94% confidence interval, CI: 0.994 - 1.16); GSD, 1.02 (94% CI: 0.946 - 1.10)). Relative bioavailabilities for EE and GSD were 31% and 24% higher, respectively, for arm vs. abdomen. AUC(0-168) 94% CI for the arm/abdomen ratio exceeded the pre-defined bioequivalence range of 80 - 125% (EE: 1.21 - 1.42; GSD: 1.15 - 1.34). Other PK parameters were correspondingly higher for arm vs. buttocks or abdomen. Patch adhesion and tolerability were good, with no relevant differences between sites.
  
  
  CONCLUSIONS
  Differences in systemic EE/GSD exposure following patch application to the outer, upper arm vs. lower abdomen and buttocks are unlikely to be clinically relevant, and there were no relevant safety concerns.
authors.forename: Joachim
authors.initials: J
authors.lastname: Höchel
authors.forename: Barbara
authors.initials: B
authors.lastname: Schuett
authors.forename: Matthias
authors.initials: M
authors.lastname: Ludwig
authors.forename: Christian
authors.initials: C
authors.lastname: Zurth
mesh_terms: D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D018592:Cross-Over Studies; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009652:Norpregnenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012738:Sex Hormone-Binding Globulin / Q000032:analysis; D057968:Transdermal Patch
chemical_list: D009652:Norpregnenes; D012738:Sex Hormone-Binding Globulin; C033273:Gestodene; D004997:Ethinyl Estradiol