Clinical Implications of Riociguat Pharmacokinetics and Pharmacodynamics: Introduction to the Riociguat Clinical Pharmacology Supplement

Riociguat (BAY 63-2521) is a novel oral soluble guanylate cyclase (sGC) stimulator developed for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). 1 It targets the nitric oxide (NO)–sGC–cyclic guanosine monophosphate (cGMP) pathway and, via a dual mode of action, both stimulates sGC directly, independently of NO, and sensitizes sGC to endogenous NO by stabilizing NO-sGC binding. As a result, riociguat restores the NO-sGC-cGMP pathway, increasing intracellular levels of cGMP,1-3 thereby addressing the imbalance of vasoconstriction over vasodilation that is present in the lung vasculature of patients with pulmonary hypertension (PH). 4 Riociguat has been evaluated in a rigorous clinical trial program, including two large randomized, double-blind, placebo-controlled phase 3 studies, PATENT-1 and CHEST-1, and their respective long-term extension studies, PATENT-2 and CHEST-2. These studies have shown that riociguat can improve exercise capacity, hemodynamic function, and quality-of-life parameters in patients with PAH or CTEPH.5-8 Data from the clinical trial program have also shown riociguat to be well tolerated and to have a favorable safety profile that was sustained over long-term treatment. Most of the observed side effects are consistent with the vasodilatory effects of the drug, such as headache, dizziness, and hypotension, and adverse events were evenly matched between riociguat and placebo treatment groups. Syncope was an adverse event of special interest, but in the two pivotal trials the incidences of serious syncope events were higher in the placebo groups than in the riociguat groups. Few patients discontinued treatment as a result of adverse events.5-10 On the basis of these studies, riociguat was the first therapy to be approved for the treatment of two indications: PAH, as demonstrated in patients with etiologies of idiopathic or heritable PAH or PAH associated with connective-tissue disease, and inoperable or persistent/recurrent CTEPH.9,10 Patients with congenital heart disease were also included in the PATENT studies.11 Riociguat is now licensed in more than 50 countries worldwide, including European countries, the United States, Canada, and Japan. Additional clinical trials are ongoing to investigate the efficacy and tolerability of riociguat in other indications, including PH associated with idiopathic interstitial pneumonia (ClinicalTrials.gov identifier: NCT02138825). In addition to the phase 3 studies, riociguat has a comprehensive clinical pharmacology portfolio based on a series of pharmacokinetic (PK) and pharmacodynamic (PD) studies. The choice of clinical pharmacology studies conducted with riociguat was guided by the PK (e.g., drug-drug interactions based on known metabolism) and PD (e.g., known hemodynamic/vasoactive activity) properties of riociguat, in addition to the typical characteristics of the PH patient population (e.g., patient covariates, such as renal/hepatic function, and potential concomitant medication use, such as warfarin). PK profiling of riociguat was of particular interest because of the observed direct link between riociguat exposure and its hemodynamic activity, as demonstrated in initial clinical pharmacology and proof-of-concept studies12,13 and later supported by a population PK and PD analysis from the phase 3 studies.14 Evidence from these studies facilitates the safe and effective use of riociguat, as reflected in the US prescribing information10 and the European summary of product characteristics,9 and helps to inform physicians making treatment decisions. This supplement includes a collection of the PK and PD studies conducted with riociguat, to provide a complete clinical pharmacology profile of the drug in both healthy volunteers and patients with PAH and CTEPH.