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Pharmacokinetic interaction of ketoconazole, clarithromycin, and midazolam with riociguat


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.


Pre- and co-treatment with ketoconazole increased riociguat mean AUC by 150% and mean Cmax by 46% (Figure 1; Table 1). Pre- and co-treatment with clarithromycin increased riociguat AUC by 41% without significantly increasing Cmax (Figure 2; Table 1). Riociguat pre- and co-treatment did not significantly alter the AUC or Cmax of midazolam (Figure 3; Table 2). In the ketoconazole study, adverse events (AEs) were reported in 4 (25%), 6 (38%), and 5 (31%) subjects treated with riociguat alone, riociguat + ketoconazole, and ketoconazole alone, respectively. In the clarithromycin study, AEs were reported in 4 (29%), 9 (64%), and 9 (64%) subjects treated with riociguat alone, riociguat + clarithromycin, and clarithromycin alone, respectively. In the midazolam study, AEs were reported in 20 (87%), 11 (48%), and 6 (27%) subjects treated with riociguat alone, riociguat + midazolam, and midazolam alone, respectively. The most common AEs with riociguat ± ketoconazole, clarithromycin, and midazolam across the three studies were headache and dyspepsia. One serious AE was reported in the midazolam study (elevated creatine phosphokinase; not drug-related).

Table 1 The effects of ketoconazole and clarithromycin on riociguat pharmacokinetics (geometric means and coefficients of variation)
Table 2 The effects of riociguat on midazolam pharmacokinetics (geometric means and coefficients of variation)
Figure 1
figure 1

Plasma concentrations of riociguat 0.5 mg alone or in combination with ketoconazole 400 mg.

Figure 2
figure 2

Plasma concentrations of riociguat 1 mg alone or in combination with clarithromycin 500 mg.

Figure 3
figure 3

Plasma concentrations of midazolam 7.5 mg alone, and in combination with riociguat 2.5 mg. LLOQ, lower limit of quantification.


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.

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Correspondence to Corina Becker.

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Corina Becker contributed equally to this work.

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Becker, C., Frey, R., Unger, S. et al. Pharmacokinetic interaction of ketoconazole, clarithromycin, and midazolam with riociguat. BMC Pharmacol Toxicol 14 (Suppl 1), P5 (2013).

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