title: 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: an open-label, single-center, first-in-human study.
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 μg (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 μg 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 non-compartmental 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 (t(max)) of 8 minutes for 45, 90, and 180 μg dose groups; the plasma concentration of BCQB decreased in a biphasic manner with the mean half-life (t(&frac12;)) of 8.5 hours; the maximum concentration (C(max)) 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.
  
  
  CONCLUSIONS
  BCQB was safe and well tolerated in healthy Chinese subjects when administered intranasally with single and multiple doses across the doses studied. The mean C(max) 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 development in the treatment of rhinorrhea in rhinitis.
authors.affiliation: China Pharmaceutical University, Nanjing, China.
authors.forename: Luning
authors.initials: L
authors.lastname: Sun
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Wang
authors.forename: Wenjia
authors.initials: W
authors.lastname: Zhou
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Yan
authors.forename: Weilin
authors.initials: W
authors.lastname: Sun
authors.forename: Hongwen
authors.initials: H
authors.lastname: Zhang
authors.forename: Ning
authors.initials: N
authors.lastname: Ou
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D002681:China; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors*; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; C518439:bencycloquidium bromide