Abstract Co‐administration of oral phosphodiesterase 5 inhibitors with oral soluble guanylate cyclase (sGC) stimulators is contraindicated due to the risk of systemic side effects. Frespaciguat, an inhaled sGC stimulator, has been studied in pulmonary hypertension (PH)‐related conditions such as pulmonary arterial hypertension (PAH) and PH associated with chronic obstructive pulmonary disease (PH‐COPD), and may allow combined use with oral PDE5i due to low systemic exposure. To evaluate a potential interaction between inhaled frespaciguat and oral sildenafil, 19 healthy participants were randomized to two treatment sequences (two periods separated by a 36‐h washout). Treatment involved 3 days of dosing with open‐label oral sildenafil (20 mg, three times per day) and a single inhaled dose of frespaciguat 240 µg or placebo on Day 3. Primary endpoints included safety assessed by adverse events (AEs) and change from baseline in systolic and diastolic blood pressure, and heart rate. Incidence of AEs was comparable across groups with no serious AEs, discontinuations due to AEs, or deaths. In conclusion, inhaled frespaciguat was well tolerated when administered on background sildenafil, without negative effects on systemic hemodynamics, versus placebo. The lack of additive systemic effects on blood pressure further documents pulmonary selectivity of inhaled frespaciguat, including when co‐administered with sildenafil (EudraCT number 2019‐001224‐35).
Bajwa et al. (Sun,) studied this question.