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 mg/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 mg); and (iv) ten subjects received 120 mg 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

Study of pharmacokinetic interaction of paroxetine and roxithromycin on bencycloquidium bromide in healthy subjects

“…Early study on safety and tolerability of BCQB showed BCQB to be tolerable in healthy volunteers up to the dose of 480 lg, which is 2.5 fold the dosage used in the current study (Sun et al, 2012). In our study, all subjects' AUC after co-administration with paroxetine were within 1.0-1.5 fold, except for two subjects with 2 fold AUC.…”

“…A series of studies have shown BCQB to be a potent drug with significant therapeutic effects on hypersensitive rhinitis, allergic rhinitis, airway-inflammation, pruritus and acute rhinitis known as common cold Xu et al, 2008;Li et al, 2011). Also, early study of BCQB in human showed its safety and tolerability after single doses escalation and multiple doses escalation (Sun et al, 2012). Our recent study showed that BCQB is metabolized mainly by CYP2D6 and also weekly by CYP3A4/5 and CYP2C19 (Agbokponto et al, 2014).…”

A sensitive LC–MS/MS method for simultaneous determination of cabozantinib and its metabolite cabozantinib N‐oxide in rat plasma and its application in a pharmacokinetic study

“…In the power model, α is the expected value of Y for a reference dose and β is the proportionality constant. Dose proportionality was declared if the calculated 90% confidence interval (CI) of β lay within the acceptance range [1 + ln(0.5)/ln( r ), 1 + ln(2.0)/ln( r )] (Sun et al, ), where r is the ratio between the highest and lowest doses in the study. In this study, the maximal dose ratio was 12.6, so the acceptance range was 0.726–1.274.…”

In vitro metabolism of bencycloquidium bromide and its inhibitory effects on human P450 isoenzymes: implication of CYP2D6, CYP2C19 and CYP3A4/5

“…Furthermore, its potential anti-inflammatory, anti-hyperreactive and antiremodeling effects on allergen-induced effects in mice asthmatic model have been described . Previous pharmacokinetic studies of this compound in rats and beagle dog after intranasal administration (Xu et al 2007(Xu et al , 2008aJiang et al 2010), and in humans using nasal spray of BCQB 45 lg (Sun et al 2012) demonstrated a long elimination half-life (11.7 ± 7.1 h) but without subchronic toxicity after a long-term toxicokinetics study of intranasal administration of BCQB in dogs ). Also, further study of BCQB in human showed its safety and tolerability after single-dose escalation and multipledose escalation (Sun et al 2012).…”

“…Previous pharmacokinetic studies of this compound in rats and beagle dog after intranasal administration (Xu et al 2007(Xu et al , 2008aJiang et al 2010), and in humans using nasal spray of BCQB 45 lg (Sun et al 2012) demonstrated a long elimination half-life (11.7 ± 7.1 h) but without subchronic toxicity after a long-term toxicokinetics study of intranasal administration of BCQB in dogs ). Also, further study of BCQB in human showed its safety and tolerability after single-dose escalation and multipledose escalation (Sun et al 2012). Cytochrome P450 enzymes are mostly involved in the metabolism and disposition of more than 60 % of currently marketed drugs and are considered central in many clinically important drug interactions (Bailey et al 1998;Lim et al 2008;Liu et al 2010).…”