Riociguat (BAY 63-2521) is the first member of a novel class of compounds, the soluble guanylate cyclase (sGC) stimulators. Riociguat has a dual mode of action: it sensitizes sGC to endogenous nitric oxide (NO) and stimulates sGC independent of NO availability. To characterize the biopharmaceutical properties of riociguat, including absolute bioavailability, food interactions, and dose proportionality, riociguat (intravenous/oral) was administered to healthy male subjects in 3 open-label, randomized, crossover studies: absolute bioavailability (1 mg; [Formula: see text]), food effect (2.5 mg; [Formula: see text]), and dose proportionality (0.5-2.5 mg; [Formula: see text]). Absolute bioavailability was 94% (95% confidence interval [CI], 83%-107%). Riociguat absorption was delayed by a high-fat breakfast with little effect on the extent of absorption (area under the concentration-time curve [AUC]fed∶AUCfasted, 88% [90% CI, 82%-95%]). Exposure to riociguat was dose proportional over all doses (common slope of AUC, 1.09 [90% CI, 1.04-1.14]; maximum concentration, 0.98 [90% CI, 0.93-1.04]). Intraindividual variability was low; interindividual variability was moderate to high. Riociguat was well tolerated, and adverse events were consistent with the mode of action. In conclusion, riociguat shows complete oral absorption, no clinically relevant food effects, and a dose-proportional increase in systemic exposure (0.5-2.5 mg). These data support the suitability of the individualized dose adjustment scheme employed in the phase 3 clinical studies.
Keywords: food interaction; pharmacokinetics; pulmonary hypertension.