title: Characterisation of the pharmacokinetics of ethinylestradiol and drospirenone in extended-cycle regimens: population pharmacokinetic analysis from a randomised Phase III study.
abstract: OBJECTIVE
  The primary objective of this analysis was to characterise the steady-state pharmacokinetics (PK) of ethinylestradiol (EE) and drospirenone (DRSP) in a randomised Phase III study that investigated the contraceptive efficacy and safety of three different regimens of EE 20&emsp14;µg/DRSP 3&emsp14;mg.
  
  
  METHODS
  Non-linear mixed-effects modelling was used to develop population PK models for EE and DRSP. EE and DRSP serum concentrations were determined in blood samples obtained from approximately 1100 healthy young women on two occasions during the first cycle (Week 3) and after 6&emsp14;months (Week 27) of EE 20&emsp14;µg/DRSP 3&emsp14;mg use. EE 20&emsp14;µg/DRSP 3&emsp14;mg was administered as a flexible extended regimen [24-120&emsp14;days' active hormonal intake followed by 4&emsp14;days with no tablet intake (tablet-free interval)], a conventional 28-day cyclic regimen (24&emsp14;days' active hormonal intake followed by 4&emsp14;days of placebo tablets) or a fixed extended regimen (120&emsp14;days' uninterrupted active hormonal intake followed by a 4-day tablet-free interval) over 1&emsp14;year.
  
  
  RESULTS
  The population PK of EE and DRSP in this population were successfully described using the developed population models. All three regimens led to similar steady-state drug exposure during long-term treatment. Only minor changes (≤ 8%) in the steady-state PK of EE and DRSP were observed between Week 3 and Week 27 of an extended regimen. Body weight (BW) and age had a small, statistically significant impact on the PK of EE and DRSP (BW only) in a covariate analysis, however, these changes were not considered to be clinically relevant.
  
  
  CONCLUSIONS
  Extending the established 24/4-day regimen of EE 20&emsp14;µg/DRSP 3&emsp14;mg does not change the known steady-state PK of EE and DRSP, suggesting that the clinical efficacy is also similar. This is in line with the published clinical results from this study.
authors.affiliation: Director PK Expert ONC, Global Drug Discovery - Clinical Sciences, Bayer HealthCare Pharmaceuticals, Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Reif
authors.forename: Nelleke
authors.initials: N
authors.lastname: Snelder
authors.forename: Hartmut
authors.initials: H
authors.lastname: Blode
mesh_terms: D000328:Adult; D000736:Androstenes / Q000097:blood / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics; D004997:Ethinyl Estradiol / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D012102:Reproductive Control Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000736:Androstenes; D003692:Delayed-Action Preparations; D012102:Reproductive Control Agents; C534342:drospirenone and ethinyl estradiol combination; D004997:Ethinyl Estradiol; C035144:drospirenone