Pharmacokinetics, Safety and Tolerability of Bencycloquidium Bromide, a Novel Selective Muscarinic M1/M3 Receptor Antagonist, After Single and Multiple Intranasal Doses in Healthy Chinese Subjects

Abstract

Background: Bencycloquidium bromide (BCQB) is a novel, potent and selective muscarinic M1/M3 receptor antagonist under development for the treatment of rhinorrhea in rhinitis. The pharmacokinetics and safety of BCQB in animals have been established in preclinical studies. However, no clinical pharmacokinetic data are available for BCQB in humans.Objective: The aim of this first-in-human study was to evaluate the pharmacokinetics, safety and tolerability of BCQB following single and multiple intranasal doses in healthy Chinese subjects.Methods: The clinical trial was comprised of the following four studies: (i) an open-label, single-dose escalation study to evaluate the safety and tolerability in healthy subjects after intranasal doses of BCQB ranging from 45 to 450 mg (total of six doses); (ii) an open-label, multiple-dose escalation study to assess the safety and tolerability in healthy subjects after intranasal administration with 120 and 150 mg doses of BCQB (360 and 450 μg/day) administered three times daily for 15 days; (iii) a randomized, open-label and parallel-group design to evaluate the single-dose pharmacokinetics of BCQB after intranasal dosing (45, 90, and 180 μg); and (iv) ten subjects received 120 μg of BCQB by intranasal administration, three times daily for 5 days with a final single dose on day 7 to assess its multiple-dose pharmacokinetics. Safety and tolerability of BCQB were evaluated by monitoring adverse events (AEs), ECG recordings, vital signs and clinical laboratory parameters. The pharmacokinetic parameters for BCQB were calculated by software using noncompartmental methods.Results: All AEs were mild, of limited duration and no more frequent at higher doses. There was no serious adverse event, death or withdrawal. No clinically significant change was noted in clinical laboratory parameters, cardiac parameters or vital signs. Following single intranasal dosing, BCQB was rapidly absorbed with a median time to maximum concentration (tmax) of 8 minutes for 45, 90, and 180 mg dose groups; the plasma concentration of BCQB decreased in a biphasic manner with the mean half-life (t1/2) of 8.5 hours; the maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) of BCQB increased linearly across the examined dose range of 45–180 μg. During the multiple dosing, the steady state was achieved within 3 days of 120 μg three times daily dosing of BCQB. A slightly greater AUC was observed after 5 days of multiple dosing, with the mean accumulation ratio of 1.26; however, the half-life was unchanged.Conclusion: BCQB was safe and well tolerated in healthy Chinese subjects when administered intranasally with single and multiple doses across the doses studied. The mean Cmax and AUC increased proportionally to the studied doses, and the steady state was achieved within 3 days after three times daily dosing. A slight accumulation of BCQB following multiple dosing was observed. The pharmacokinetics, safety and tolerability profiles of BCQB pose it as a good candidate for further deve...

Effects of ABCB1, UGT1A1, and UGT1A9 Genetic Polymorphisms on the Pharmacokinetics of Sitafloxacin Granules in Healthy Subjects

“…A regression coefficient at a level of 0.1 was considered significant. This study used a predefined standard of (0.5, 2.0) 21,22 and a standard interval of (0.500, 1.500). Across the different dose groups, the relevant PK parameters were calculated using an analysis of variance (ANOVA) except for T max , which was calculated using a nonparametric test.…”

<p>Long-Acting Muscarinic Antagonists Under Investigational to Treat Chronic Obstructive Pulmonary Disease</p>

“…24 In mice sensitized and challenged with ovalbumin to develop airway inflammation, inhalation administration of BCQB significantly reduced ovalbumininduced airway hyperresponsiveness and prevented the ovalbumin-induced increase in total cell counts and eosinophil counts. 25 An intranasal formulation of BCQB has been developed for the treatment of rhinorrhoea and is under clinical evaluation. BCQB proved to be safe and well tolerated in healthy Chinese subjects when administered intranasally with single and multiple doses across the doses studied.…”

Liquid Chromatography Tandem Mass Spectrometry Determination Method of Bencycloquidium Bromide: Application to Drug Interaction Study in Human

“…Studies on general pharmacological actions of BCQB suggested that it had no obvious effect on cardiovascular and respiratory in beagle dogs, and could decrease the extraction of the bronchus gland and inhibit the peristalsis of the small intestine in mice [4,5]. Under the clinical trial, an early study has shown its tolerability and efficacy [6]. However, the investigations of drug interactions of BCQB in humans remain an important part of its safety.…”