- Poster presentation
- Open Access
Pharmacokinetic interaction of ketoconazole, clarithromycin, and midazolam with riociguat
- Corina Becker†1Email author,
- Reiner Frey1,
- Sigrun Unger2,
- Dirk Thomas1,
- Michael Reber1,
- Gerrit Weimann1,
- Hartmut Dietrich3,
- Erich R Arens1 and
- Wolfgang Mueck1
© Becker et al; licensee BioMed Central Ltd. 2013
- Published: 29 August 2013
- Pulmonary Hypertension
- Guanylate Cyclase
Riociguat, an oral soluble guanylate cyclase stimulator, is under investigation for pulmonary hypertension treatment. Cytochrome P450 (CYP)-mediated oxidative metabolism is one of the major riociguat clearance pathways. The pharmacokinetic interactions between riociguat and ketoconazole (multi-pathway CYP and P-glycoprotein/breast cancer resistance protein [P-gp/BCRP] inhibitor), clarithromycin (CYP3A4 inhibitor), and midazolam (CYP3A4 substrate) were investigated.
Three open-label, randomized, crossover studies were performed in healthy males. In the first study, subjects received riociguat 0.5 mg ± ketoconazole (4-day pretreatment with once-daily [od] ketoconazole 400 mg, then riociguat + 1 dose of ketoconazole 400 mg) (n=16). In the second study, subjects received riociguat 1 mg ± clarithromycin (4-day pretreatment with twice-daily clarithromycin 500 mg, then riociguat + 1 dose of clarithromycin 500 mg) (n=14). In the third study, subjects received three-times daily (tid) riociguat 2.5 mg for 3 days, then 1 day of riociguat 2.5 mg tid ± midazolam 7.5 mg (n=24). Pharmacokinetic parameters, safety, and tolerability were assessed.
The effects of ketoconazole and clarithromycin on riociguat pharmacokinetics (geometric means and coefficients of variation)
Riociguat 0.5 mg (n=16)
Riociguat 0.5 mg + ketoconazole (n=16)
Riociguat 1 mg (n=14)
Riociguat 1 mg + clarithromycin (n=14)
The effects of riociguat on midazolam pharmacokinetics (geometric means and coefficients of variation)
Midazolam + riociguat 2.5 mg (n=22)
The combined use of riociguat with multi-pathway inhibitors such as anti-mycotics (eg ketoconazole) or HIV protease inhibitors should be avoided due to the expected increase in riociguat exposure. General dose adaptation for patients with co-medication inhibiting the CYP3A4 pathway or the P-gp/BCRP-mediated excretion of riociguat, beyond the dose titration concept for riociguat, is not deemed necessary. Riociguat ± ketoconazole, clarithromycin, or midazolam was generally well tolerated.
The studies were funded by Bayer HealthCare Pharmaceuticals, Wuppertal, Germany. Medical writing assistance was provided by Adelphi Communications Ltd, Bollington, UK and funded by Bayer HealthCare Pharmaceuticals.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.