Pharmacokinetic interaction between ethinyl estradiol, norethindrone and darunavir with low-dose ritonavir in healthy women.
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.
Sekar
Vanitha J
VJ
Tibotec, Inc., Yardley, PA, USA. vsekar@tibus.jnj.com
Lefebvre
Eric
E
Guzman
Sabrina Spinosa
SS
Felicione
Elise
E
De Pauw
Martine
M
Vangeneugden
Tony
T
Hoetelmans
Richard M W
RM
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*
D003276:Contraceptives, Oral; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D004997:Ethinyl Estradiol; D019438:Ritonavir; D009640:Norethindrone; D000069454:Darunavir