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First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension

¹ Dept of Internal Medicine, University Hospital Giessen and Marburg, , Giessen, ² Clinical Pharmacology, and ³ Global Biostatistics, Bayer HealthCare AG, Pharma Research Centre, Wuppertal, Germany.

CORRESPONDENCE: H.A. Ghofrani, Dept of Internal Medicine, Medical Clinic II/V, University Hospital Giessen and Marburg GmbH, Klinikstrasse 36, 35392 Giessen, Germany. Fax: 49 6419942419. E-mail: ardeschir.ghofrani{at}innere.med.uni-giessen.de

Keywords: Maximum tolerated dose, pharmacokinetics, phase-II clinical trial, pulmonary hypertension, soluble guanylyl cyclase, vasodilation

Received: March 14, 2008
Accepted November 21, 2008

Pulmonary hypertension (PH) is associated with impaired production of the vasodilator nitric oxide (NO). Riociguat (BAY 63-2521; Bayer Healthcare AG, Wuppertal, Germany) acts directly on soluble guanylate cyclase, stimulating the enzyme and increasing sensitivity to low NO levels. The present study evaluates riociguat safety, tolerability and efficacy in patients with moderate-to-severe PH (pulmonary arterial hypertension, distal chronic thromboembolic PH or PH with mild to moderate interstitial lung disease).

The optimal tolerated dose was identified by incremental dosing in four patients with PH; pharmacodynamic and pharmacokinetic parameters were assessed following single-dose administration (2.5 mg or 1 mg) in 10 and five patients with PH, respectively. All subjects (n = 19) were analysed for safety and tolerability.

Riociguat had a favourable safety profile at single doses 2.5 mg. It significantly improved pulmonary haemodynamic parameters and cardiac index in patients with PH in a dose-dependent manner, to a greater extent than inhaled NO. Although riociguat also had significant systemic effects and showed no pulmonary selectivity, mean systolic blood pressure remained >110 mmHg.

The present report is the first to describe the use of riociguat in patients with pulmonary hypertension. The drug was well-tolerated and superior to nitric oxide in efficacy and duration. Riociguat, therefore, has potential as a novel therapy for pulmonary hypertension and warrants further investigation.

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