title: Pharmacokinetic overview of ethinyl estradiol dose and bioavailability using two transdermal contraceptive systems and a standard combined oral contraceptive.
abstract: OBJECTIVE
  To determine the relative bioavailability of ethinyl estradiol (EE) and gestodene (GSD) after application of a novel transdermal contraceptive patch vs. a standard combined oral contraceptive (COC) pill (study 1), and to evaluate the pharmacokinetics (PK) of EE after application of the EE/GSD patch compared with an EE/norelgestromin (NGMN) patch (study 2).
  
  
  METHODS
  Participants were healthy, nonobese women aged 18 - 45 years (study 1) or 18 - 35 years (study 2). Compositions of study treatments were as follows: 0.55 mg EE/2.1 mg GSD (EE/GSD patch); 0.02 mg EE/0.075 mg GSD (standard COC); 0.6 mg EE/6 mg NGMN (EE/NGMN patch).
  
  
  METHODS
  In study 1, which consisted of 3 treatment periods (each followed by 7 patch- or pill-free days), treatments were administered in one of two randomized orders: either P-M-E (EE/GSD patch (P) every 7 days for 28 days → COC (M) once-daily for 21 days → two 7-day patch-wearing periods followed by one 10-day patch-wearing phase (E)), or the same treatments administered in sequence M-P-E. For study 2, participants received either the EE/GSD patch or EE/NGMN patch for seven treatment cycles (one patch per week for 3 weeks followed by a 7-day patch-free interval).
  
  
  RESULTS
  In study 1, average daily exposure to EE was similar for treatments P and M; the mean daily area under the concentration-time curve (AUC) ratio of treatment P vs. treatment M for EE was 1.06 (90% confidence interval (CI): 0.964 - 1.16), indicating average daily delivery similar to oral administration of 0.019 - 0.023 mg EE. For unbound GSD, average daily exposure was lower for treatment P vs. treatment M. The mean AUC ratio of treatment P vs. treatment M for unbound GSD was 0.820 (90% CI: 0.760 - 0.885), indicating average daily delivery from the patch of 0.057 - 0.066 mg GSD. Prolonged patch wearing did not result in a distinct decline in GSD and EE serum concentrations. In study 2, AUC at steady state (AUC0-168,ss), average steady-state serum concentration, and maximum steady-state serum concentration for EE was 2.0 - 2.7-fold higher for the EE/NGMN patch vs. the EE/GSD patch. The EE/GSD patch was well tolerated in both studies.
  
  
  CONCLUSIONS
  Based on the 90% CI of the AUC ratio of oral treatment vs. patch application for unbound GSD and EE, the daily doses of GSD and EE released from the EE/GSD patch over the 7-day application period provided the same systemic exposure as those recorded after daily oral administration of a COC containing 0.02 mg EE and 0.06 mg GSD. The EE/GSD patch showed reduced EE exposure compared with the EE/NGMN patch. Together with its good tolerability, these properties support the EE/GSD patch as an effective and well-tolerated alternative to available transdermal and oral contraceptives.
authors.forename: Birte
authors.initials: B
authors.lastname: Hofmann
authors.forename: Isabel
authors.initials: I
authors.lastname: Reinecke
authors.forename: Barbara
authors.initials: B
authors.lastname: Schuett
authors.forename: Martin
authors.initials: M
authors.lastname: Merz
authors.forename: Christian
authors.initials: C
authors.lastname: Zurth
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D003277:Contraceptives, Oral, Combined / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D009652:Norpregnenes / Q000008:administration & dosage / Q000009:adverse effects; D057968:Transdermal Patch
chemical_list: D003277:Contraceptives, Oral, Combined; D009652:Norpregnenes; C033273:Gestodene; D004997:Ethinyl Estradiol