Background

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.

Methods

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.

Results

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

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

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Figure 2
figure 2

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

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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.

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Conclusions

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.