Pulmonary hypertension is a life-threatening condition with limited therapeutic options. Riociguat, a soluble guanylate cyclase stimulator, is approved for pulmonary arterial and chronic thromboembolic pulmonary hypertension, but oral administration results in variable systemic exposure and adverse effects. This study aimed to evaluate the intratracheal pharmacokinetics and pulmonary retention of riociguat in mice, comparing a suspension and a dimethyl sulfoxide (DMSO)-based solution.Pharmacokinetic parameters, including maximum concentration (Cmax), time to maximum concentration (Tmax), half-life (t1/2), mean residence time (MRT), systemic exposure, and tissue distribution (lung, kidney, and liver), were determined. Lung histology was also assessed.The solution demonstrated higher dose-corrected plasma Cmax (0.278 vs. 0.128 ng/mL/ug) and shorter systemic retention (MRT0-∞: 3.57 vs. 4.43 h) compared with the suspension, while systemic exposure remained similar. In lung tissue, the suspension exhibited prolonged retention with longer t1/2 (13.54 vs. 5.17 h) and MRT0-∞ (13.37 vs. 7.82 h), indicating sustained pulmonary exposure. No histological changes were observed with the DMSO-based formulation. The suspension provided extended lung retention but contained large particles (10-100 μm) unsuitable for inhalation. Particle engineering to develop optimized suspension or dry powder formulations may enable efficient lung deposition and improve riociguat inhalation therapy.
Zhang et al. (Wed,) studied this question.