Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol.
OBJECTIVE
Bosentan has been shown in vitro and in vivo to induce the cytochrome P450 enzymes CYP2C9 and CYP3A4. The present study was conducted to investigate the effect of bosentan on the pharmacokinetics of a combined oral contraceptive.


METHODS
In a randomized, 2-way crossover study, 20 healthy female subjects received Treatments A and B. Treatment A consisted of a single dose of OrthoNovum containing 1 mg norethisterone (norethindrone) and 35 microg ethinyl estradiol. Treatment B consisted of bosentan, 125 mg b.i.d. for 7 days plus concomitant norethisterone and ethinyl estradiol on Day 7. Plasma concentrations of norethisterone and ethinyl estradiol were measured on days of oral contraceptive administration.


RESULTS
In the absence of bosentan, the pharmacokinetics of norethisterone and ethinyl estradiol were characterized by Cmax and AUC0-infinity values (95% CI) of 9.8 (8.1, 11.9) ng/ml and 72.9 (57.0, 93.1) ng x h/ml, and 53.0 (47.0, 59.9) pg/ml and 758 (655, 878) pg x h/ml, respectively. Concomitant bosentan did not affect the Cmax but significantly decreased the AUC of norethisterone and ethinyl estradiol by 13.7% (-23.5, -2.6) and 31.0% (-40.5,-20.2), respectively. The maximum decrease in AUC of norethisterone and ethinyl estradiol in an individual subject was 56% and 66%, respectively.


CONCLUSIONS
Bosentan decreases the AUC of norethisterone and ethinyl estradiol in healthy female subjects. In patients treated with bosentan, reduced efficacy of hormonal contraceptives should be considered.
Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. paul.vangiersbergen@actelion.com
P L M
PL
van Giersbergen
A
A
Halabi
J
J
Dingemanse
D000328:Adult; D000959:Antihypertensive Agents / Q000494:pharmacology*; D019540:Area Under Curve; D000077300:Bosentan; D003277:Contraceptives, Oral, Combined / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004336:Drug Antagonism; D004997:Ethinyl Estradiol / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D009640:Norethindrone / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000494:pharmacology*
D000959:Antihypertensive Agents; D003277:Contraceptives, Oral, Combined; D013449:Sulfonamides; D004997:Ethinyl Estradiol; D000077300:Bosentan; D009640:Norethindrone