Effects of omeprazole and AlOH/MgOH on riociguat absorption

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.

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.

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.

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.

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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).

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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.

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.

Author notes

Affiliations

1. Clinical Pharmacology, Bayer HealthCare Pharmaceuticals, Wuppertal, Germany

   • Corina Becker
   • , Reiner Frey
   • , Ulrike Artmeier-Brandt
   • , Gerrit Weimann
   •  & Wolfgang Mueck

2. Global Biostatistics, Bayer HealthCare Pharmaceuticals, Wuppertal, Germany

   • Sigrun Unger

Corresponding author

Correspondence to Corina Becker.

Corina Becker contributed equally to this work.

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