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.