Effects of omeprazole and AlOH/MgOH on riociguat absorption

Background

Riociguat, a soluble guanylate cyclase stimulator, is currently under investigation for the treatment of pulmonary hypertension. The present studies investigated the influence of omeprazole and AlOH/MgOH on riociguat absorption and bioavailability.

Methods

The pharmacokinetics of oral, single-dose, immediate-release riociguat 2.5 mg were characterized in two open-label, randomized, crossover studies in healthy males. In the first study, subjects pretreated for 4 days with once-daily omeprazole 40 mg received co-treatment with omeprazole + riociguat or riociguat alone (no pretreatment) on Day 5 (n=12). In the second study, subjects received co-treatment with 10 mL AlOH/MgOH + riociguat or riociguat alone (n=12). Pharmacokinetic characteristics were analyzed assuming log-normally distributed data. Safety and tolerability were also assessed.

Results

Riociguat bioavailability was decreased by pre- and co-treatment with omeprazole, with a mean decrease in C_max of 35% and a mean decrease in AUC of 26% (Table 1; Figure 1). Co-treatment with 10 mL AlOH/MgOH resulted in a mean decrease in C_max of 56% and a mean decrease in AUC of 34% (Table 1; Figure 2). In the riociguat/omeprazole study, adverse events (AEs) were reported in 4 (33%) subjects receiving riociguat alone and in 5 (42%) subjects receiving riociguat + omeprazole, with no AEs reported during the omeprazole pretreatment phase. The most commonly reported AEs were headache (9 events in 8 subjects; 5 drug-related events) and flushing (3 events in 2 subjects; all drug-related). In the riociguat/AlOH/MgOH study, AEs were reported in 9 (75%) subjects receiving riociguat alone and in 8 (67%) subjects receiving riociguat + AlOH/MgOH. The most commonly reported AEs were headache (12 events in 7 subjects; all drug-related), rhinitis (3 events in 3 subjects; no drug-related events), nasal congestion (3 events in 2 subjects; 2 drug-related events), and upper abdominal pain (3 events in 2 subjects; no drug-related events). No serious AEs were reported in either study and all AEs resolved by the end of the observation period.

Table 1 Riociguat pharmacokinetic parameters (geometric means and coefficients of variation)

Figure 1

Riociguat plasma concentrations after a single oral dose of riociguat 2.5 mg with and without pre- and co-treatment with once-daily omeprazole 40 mg (geometric means, semilogarithmic scale; all subjects valid for pharmacokinetics; n=12). IR, immediate release.

Figure 2

Riociguat plasma concentrations after a single oral dose of riociguat 2.5 mg with and without co-administration of 10 mL AlOH/MgOH (geometric means, semilogarithmic scale; all subjects valid for pharmacokinetics; n=12).

Conclusion

Treatment with riociguat, with or without omeprazole or AlOH/MgOH, was well tolerated, with a good safety profile. The results confirm the lower bioavailability of riociguat in neutral versus acidic medium as expected from in vitro data. For co-medication of antacids like AlOH/MgOH, staggered intake between riociguat and antacid is practically possible and may be advisable. A general dose adaptation for patients with co-medication acting on gastric acidity, beyond the dose titration concept for riociguat, is not recommended.