title: Pharmacokinetic interaction study between riociguat and the combined oral contraceptives levonorgestrel and ethinylestradiol in healthy postmenopausal women.
abstract: Female patients requiring treatment for pulmonary arterial hypertension (PAH) are advised to avoid pregnancy because of the high associated mortality rate. Oral contraception is one of the main methods of preventing pregnancy in this context, mandating pharmacokinetic and safety studies for new agents in this setting. Riociguat is a soluble guanylate cyclase stimulator approved for treatment of PAH and inoperable and persistent or recurrent chronic thromboembolic pulmonary hypertension. This single-center, randomized, nonblinded study involving healthy postmenopausal women investigated the effect of riociguat on plasma concentrations of levonorgestrel (0.15 mg) and ethinylestradiol (0.03 mg) in a combined oral contraceptive. Treatment A was a single oral tablet of levonorgestrel-ethinylestradiol. In treatment B, subjects received 2.5 mg riociguat 3 times daily for 12 days. On the eighth day, they also received a single oral tablet of levonorgestrel-ethinylestradiol. Subjects received both regimens in a crossover design. There was no change in area under the plasma concentration-time curves of levonorgestrel or ethinylestradiol or maximum concentration in plasma (C max) of levonorgestrel during combined administration versus levonorgestrel-ethinylestradiol alone. A 20% increase in the C max of ethinylestradiol was noted during coadministration; this is not anticipated to adversely impact the contraceptive efficacy or to require any dose adjustment for ethinylestradiol. Plasma concentrations and exposures of riociguat were within the expected range and were not influenced by coadministration with levonorgestrel-ethinylestradiol. Combined treatment was safe and well tolerated. In conclusion, riociguat did not change the exposure to levonorgestrel or ethinylestradiol relative to oral contraceptive administered alone.
authors.affiliation: Clinical Pharmacology, Pharma Research Center, Bayer Pharma, Wuppertal, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Frey
authors.affiliation: Global Biostatistics, Pharma Research Center, Bayer Pharma, Wuppertal, Germany.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Unger
authors.affiliation: Clinical Pharmacology, Pharma Research Center, Bayer Pharma, Wuppertal, Germany.
authors.forename: Dorina
authors.initials: D
authors.lastname: van der Mey
authors.affiliation: Clinical Pharmacology, Pharma Research Center, Bayer Pharma, Wuppertal, Germany.
authors.forename: Corina
authors.initials: C
authors.lastname: Becker
authors.affiliation: Clinical Pharmacology, Pharma Research Center, Bayer Pharma, Wuppertal, Germany.
authors.forename: Soundos
authors.initials: S
authors.lastname: Saleh
authors.affiliation: Clinical Pharmacology, Pharma Research Center, Bayer Pharma, Wuppertal, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Wensing
authors.affiliation: Clinical Pharmacology, Pharma Research Center, Bayer Pharma, Wuppertal, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mück
keywords: CYP3A4; drug-drug interaction; levonorgestrel-ethinylestradiol; pulmonary hypertension; soluble guanylate cyclase stimulator; steady state