title: Population pharmacokinetic/pharmacodynamic evaluation of low-dose drospirenone with 17β-estradiol in postmenopausal women with moderate to severe vasomotor symptoms.
abstract: OBJECTIVE
  This study aims to characterize the pharmacokinetics/pharmacodynamics of drospirenone and estradiol in the treatment of postmenopausal women with moderate to severe vasomotor symptoms and to explore the relationship between the serum exposures of estradiol and drospirenone and efficacy, measured by reductions in moderate to severe hot flushes.
  
  
  METHODS
  Participants in a 12-week, double-blind, randomized, placebo-controlled study of daily drospirenone/estradiol in two low-dose combinations (0.25 mg/0.5 mg and 0.5 mg/0.5 mg), estradiol (0.3 mg), or placebo provided infrequent serum samples for pharmacokinetic analysis of estradiol and drospirenone, with additional frequent sampling during 24 hours in a study subset.
  
  
  RESULTS
  Estradiol steady-state serum concentrations were described by a one-compartmental model with first-order elimination and zero-order absorption. The pharmacokinetics of drospirenone was described by a linear open two-compartment model with first-order elimination kinetics from the central compartment and delayed first-order absorption kinetics. A total of 1,516 serum estradiol concentrations and 736 serum drospirenone concentrations (n = 251) from 383 women were evaluated. Baseline estradiol concentrations increased with rising body mass index, and apparent clearance of estradiol at steady state was 39% higher in smokers versus nonsmokers. The serum exposures of both estradiol and drospirenone affected efficacy, as analyzed by a generalized linear model. Smoking had a negative effect on the efficacy of hormone therapy.
  
  
  CONCLUSIONS
  The efficacy of low-dose drospirenone/estradiol for reducing vasomotor symptoms correlates with the serum exposure of estradiol and, for the first time, the serum exposure of drospirenone. Smoking adversely affects the clearance of estradiol and the efficacy of treatment.
authors: From 1Bayer Pharma AG, Berlin, Germany; 2Gynecology, Obstetrics, and Reproductive Medicine, University Medical School of Saarland, Homburg/Saar, Germany; and 3Clinical Research Center, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA.
authors: Gabriele
authors: G
authors: Sutter
authors: Thomas
authors: T
authors: Schmelter
authors: Kerstin
authors: K
authors: Gude
authors: Matthias
authors: M
authors: Schaefers
authors: Christoph
authors: C
authors: Gerlinger
authors: David F
authors: DF
authors: Archer
mesh_terms: D000328:Adult; D000736:Androstenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015992:Body Mass Index; D004311:Double-Blind Method; D004958:Estradiol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D019584:Hot Flashes / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists; D010919:Placebos; D017698:Postmenopause; D012907:Smoking / Q000009:adverse effects
chemical_list: D000736:Androstenes; D000451:Mineralocorticoid Receptor Antagonists; D010919:Placebos; D004958:Estradiol; C035144:drospirenone