Pharmacokinetics and Lung Deposition After Administration of Inhaled Mosliciguat (BAY 1237592): Results from Randomized Phase I Studies in Healthy Men Pharmacokinetics and Lung Deposition of Inhaled Mosliciguat (BAY 1237592) in Healthy Men

• Published in: Clinical pharmacokinetics Vol. 64; no. 6; pp. 909 - 924
• Main Authors: Saleh, Soundos, Mundry, Tobias, Nagelschmitz, Johannes, Buetehorn, Ulf, Holzschuh, Stephan, Nikkho, Sylvia M.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2025
• Subjects: Internal Medicine; Medicine; Medicine & Public Health; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-025-01503-6

Background and Objective Mosliciguat is the first soluble guanylate cyclase activator designed for dry powder inhalation. It is currently under development for the treatment of pulmonary hypertension; the inhaled route of administration delivers the drug to the pulmonary vasculature with the aim of improving pulmonary hemodynamics. We conducted three phase I trials in healthy male volunteers to characterize the pharmacokinetic profile of mosliciguat, focusing on lung deposition after inhalation with a low-resistance device in a lactose carrier-based dry powder formulation. Methods Study 1 was a randomized, open-label, four-way crossover study (Part 2) comparing the pharmacokinetics of mosliciguat by inhalation (1000 μg), inhalation (1000 μg) with charcoal block, in oral solution (1000 μg), and intravenously (100 μg). (The oral and intravenous doses were selected in Part 1 of the study.) Study 2 was an 8-day, randomized, single-blind, placebo-controlled, multiple-dose escalation study of once-daily inhaled mosliciguat (480, 1000, and 2000 μg). Study 3 was a 2-week, multiple-dose, randomized, placebo-controlled, single-blind study of once-daily inhaled mosliciguat 1000 μg. Results In Study 1 (Part 2) the absolute bioavailability of inhaled mosliciguat was 18.8% without charcoal block and 16.3% with charcoal block. The absolute bioavailability of oral mosliciguat was 23.1%. Pharmacokinetic parameters showed low-to-moderate inter-subject variability. Time to maximum plasma concentration ( t max ) was 2.0 h after inhalation and 1.0 h after oral administration; half-life was 15.1 and 4.4 h, respectively. Based on accumulation ratios in Study 2, the area under the concentration−time curve (AUC) and maximum plasma concentration ( C max ) increased by 45–51% and 15–21%, respectively, across doses at day 8. In Study 2 the half-life of inhaled mosliciguat with multiple dosing was 57.4 and 42.3 h at doses of 1000 and 2000 µg, respectively. Data showed moderate variability in AUC and C max (geometric coefficients of variation, 26.6% and 24.7%, respectively, in study 3 on day 1). Trough levels showed accumulation ratios of 1.7−2.1 in Study 2 (day 8) and 2.5 in Study 3 (day 14). In all three studies, mosliciguat was well tolerated, without major systemic effects on heart rate or blood pressure. Conclusions Inhaled mosliciguat had a longer t max and half-life than oral mosliciguat. Accumulation data suggest formation of a mosliciguat depot in the lungs and continuous transfer to the systemic circulation, with an indication of an increase in accumulation ratio with longer duration of treatment. Plain Language Summary Soluble guanylate cyclase (sGC) is an enzyme that regulates biochemical processes. Reduced sGC activity can lead to a number of serious health conditions, including pulmonary hypertension (in which the blood vessels in the lungs become narrower, impairing the flow of blood through the lungs) and heart failure. Drugs that can increase sGC activity have therefore been developed. Mosliciguat is the first sGC activator designed to be given via an inhaler, with the potential to reach the lungs directly. In this paper we present results from three studies in healthy male volunteers that show the behavior of mosliciguat in the body and its deposition in the lungs after inhalation. The results show that mosliciguat remains in the body for longer when given as an inhalation than when given orally or intravenously. Overall, the results suggest that when mosliciguat is inhaled, it forms a deposit in the lungs from which the drug is slowly released without any serious side effects being observed. Based on these results, mosliciguat is suitable for an inhaled therapy.