Safety, Tolerability and Pharmacokinetics of The Phosphodiesterase 3/4 (PDE3/4) Inhibitor TQC3721 Suspension for Inhalation in Healthy Adult Subjects

Background: TQC3721 is a PDE3/4 inhibitor, which can simultaneously achieve bronchial smooth muscle relaxation and anti-inflammatory effects. Objectives: To assess the safety, tolerability and pharmacokinetics of TQC3721 in healthy adult subjects. Methods: This randomized, double-blind, placebo-controlled, phase I study consisted of 6 single ascending-dose cohorts (SAD,0.2mg,1mg,3mg,6mg,12mg,24mg), 1 multiple dose cohort (12mg once daily for 7 days) and 1 pulmonary deposition cohort(2-period crossover design in the 3mg cohort of the SAD study, with and without charcoal block). Safety, tolerability, and pharmacokinetic data were collected. Results: 64 healthy subjects were enrolled in this study (8 on active and 2 on placebo per cohort, except for the 0.2mg cohort with all 4 on active). No dose-limiting toxicities, SAEs or grade 3 AE were observed. Only 1 subject experienced a grade 2 AE of anemia, all other AEs were of grade 1. Nausea and vomiting were not observed at all doses. The incidence and severity of AEs were not dose dependent. No AEs led to treatment discontinuation. After single doses of TQC3721, C_max was reached at a median of 0.25-0.5 hour with the t_1/2 of 32.9-49.4 hours. AUC_0-t showed near-dose proportionality. Repeat dosing for 7 days showed exposures 2.59 fold (AUC_0-24h) and 1.53 fold (C_max) higher than on the single dose. The AUC_0-t and C_max were similar in the presence/absence of charcoal, with a ratio of 0.96 and 1.13, respectively. Conclusions: TQC3721 showed a favorable safety, tolerability and pharmacokinetic profile. These results support further development of TQC3721 in patients with COPD.