title: Pharmacokinetic interaction between ethinyl estradiol, norethindrone and darunavir with low-dose ritonavir in healthy women.
abstract: BACKGROUND
  An open-label, randomized, crossover study was performed to investigate the effect of multiple doses of darunavir co-administered with low-dose ritonavir (DRV/r) on the steady-state pharmacokinetics of the oral contraceptives ethinyl estradiol (EE) and norethindrone (NE) (commercial name of the combined drug Ortho-Novum 1/35) in 19 HIV-negative healthy women.
  
  
  METHODS
  In session 1, participants received 35 microg EE and 1.0 mg NE from days 1 to 21. In session 2, participants received the same oral contraceptive treatment as in session 1 on days 1 to 21 plus DRV/r (600 mg/100 mg twice daily) on days 1 to 14. Pharmacokinetic assessments were performed on day 14 for each session.
  
  
  RESULTS
  Steady-state systemic exposure to EE and NE decreased when DRV/r was co-administered, based on the ratio of least square means of the minimum plasma concentration (Cmin), the maximum plasma concentration (Cmax), and the area under the curve (AUC24h) of EE (which decreased by 62%, 32% and 44%, respectively) and NE (which decreased by 30%, 10% and 14%, respectively) compared with administration of EE and NE alone. Five participants discontinued the study due to grade 2 cutaneous events, as required per protocol, during treatment with EE and NE in combination with DRV/r. There were no clinically relevant findings for laboratory and cardiovascular parameters.
  
  
  CONCLUSIONS
  The pharmacokinetic interaction observed here is considered to be clinically relevant as EE concentrations are considerably reduced when DRV/r is co-administered with EE and NE. Alternative or additional contraceptive measures should be used when oestrogen-based contraceptives are co-administered with DRV/r.
authors.affiliation: Tibotec, Inc., Yardley, PA, USA. vsekar@tibus.jnj.com
authors.forename: Vanitha J
authors.initials: VJ
authors.lastname: Sekar
authors.forename: Eric
authors.initials: E
authors.lastname: Lefebvre
authors.forename: Sabrina Spinosa
authors.initials: SS
authors.lastname: Guzman
authors.forename: Elise
authors.initials: E
authors.lastname: Felicione
authors.forename: Martine
authors.initials: M
authors.lastname: De Pauw
authors.forename: Tony
authors.initials: T
authors.lastname: Vangeneugden
authors.forename: Richard M W
authors.initials: RM
authors.lastname: Hoetelmans
mesh_terms: D000293:Adolescent; D000328:Adult; D003276:Contraceptives, Oral / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D000069454:Darunavir; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018023:HIV Seronegativity; D006801:Humans; D009640:Norethindrone / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D003276:Contraceptives, Oral; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D004997:Ethinyl Estradiol; D019438:Ritonavir; D009640:Norethindrone; D000069454:Darunavir