Safety, Tolerability and Pharmacokinetics of Bencycloquidium Bromide, a Novel Inhaled Anticholinergic Bronchodilator, in Healthy Subjects: Results from Phase I Studies

Abstract

Background: Bencycloquidium bromide (BCQB) is a novel inhaled anticholinergic bronchodilator with high selectivity for muscarinic M3 receptor. BCQB's potential utility of for therapy in Chronic obstructive pulmonary disease (COPD) has been indicated in pre-clinical studies.

Purpose: To investigate the initial safety, tolerability and pharmacokinetics of BCQB delivered via pressurised Metered Dose Inhaler (pMDI) in healthy subjects.

Methods: This study consisted of single-ascending-dose (SAD), multiple-ascending-dose (MAD) tolerability study periods, and single- plus multiple-dose pharmacokinetic study periods. Randomized, double-blind, placebo-controlled, dose-escalating tolerability and pharmacokinetic studies were conducted. Seventy-two healthy subjects were assigned 3:1 (BCQB: placebo) to 7 single-dose cohorts (125, 250, 500, 750, 1125, 1500 and 2000 μg) and 2 multiple-dose cohorts (1500 μg/d and 2000 μg/d). In the pharmacokinetic periods, 12 subjects were allocated three-way crossover to receive single dose of 250, 750 or 2000 μg BCQB, respectively. Subsequently, the same 12 subjects received multiple dose of 750 μg/d and 1000 μg/d for 7 days. Pharmacokinetic, safety and tolerability assessments were performed.

Results: BCQB administered by inhalation was well tolerated, especially with favorable cardiovascular safety profile. BCQB was rapidly absorbed into plasma after inhalation through pMDI, with peak concentrations achieved within 5 to 10 minutes. Repeated inhalation caused certain degree of accumulation with the accumulation ratio R_Cmax 2.50, R_AUC 3.49 for 3 times-a-day and R_Cmax 2.23, R_AUC 3.44 for 4 times-a-day, respectively. Twice-a-day or even once-a-day dosage could be suggested in phase II study. Sex didn't affect the pharmacokinetics of BCQB and dose adjustments based on sex is not anticipated in clinical use. Approximately 4% of the BCQB dose excreted unchanged in urine and liver metabolism is the main biotransformation route of BCQB in human.

Conclusions: The results of our study provided the initial safety, tolerability and pharmacokinetic profiles of BCQB inhalation, and could enable further clinical development in COPD patients.

Keywords: Anticholinergic bronchodilator; Bencycloquidium bromide; Pharmacokinetics; Phase I; Tolerability.