PMID- 22339483
OWN - NLM
STAT- MEDLINE
DCOM- 20120723
LR  - 20211021
IS  - 1179-6901 (Electronic)
IS  - 1174-5886 (Print)
IS  - 1174-5886 (Linking)
VI  - 12
IP  - 1
DP  - 2012 Mar 1
TI  - 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.
PG  - 17-28
LID - 10.2165/11599330-000000000-00000 [doi]
AB  - 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 mug 
      (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 mug doses of BCQB (360 and 450 mug/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 mug); and (iv) ten subjects received 120 mug 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 mug dose groups; the plasma concentration of BCQB decreased in a 
      biphasic manner with the mean half-life (t(½)) 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 mug. During 
      the multiple dosing, the steady state was achieved within 3 days of 120 mug 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 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.
FAU - Sun, Luning
AU  - Sun L
AD  - China Pharmaceutical University, Nanjing, China.
FAU - Ding, Li
AU  - Ding L
FAU - Wang, Yongqing
AU  - Wang Y
FAU - Zhou, Wenjia
AU  - Zhou W
FAU - Yan, Zhengyu
AU  - Yan Z
FAU - Sun, Weilin
AU  - Sun W
FAU - Zhang, Hongwen
AU  - Zhang H
FAU - Ou, Ning
AU  - Ou N
FAU - Chen, Xiaoping
AU  - Chen X
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - New Zealand
TA  - Drugs R D
JT  - Drugs in R&D
JID - 100883647
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - 0 (Muscarinic Antagonists)
RN  - 0 (Receptor, Muscarinic M1)
RN  - 0 (Receptor, Muscarinic M3)
RN  - 0 (bencycloquidium bromide)
SB  - IM
MH  - Administration, Intranasal
MH  - Adult
MH  - Bridged Bicyclo Compounds, Heterocyclic/administration & dosage/*adverse 
      effects/blood/*pharmacokinetics
MH  - China
MH  - Dose-Response Relationship, Drug
MH  - Drug Administration Schedule
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Molecular Structure
MH  - Muscarinic Antagonists/administration & dosage/*adverse 
      effects/blood/*pharmacokinetics
MH  - Receptor, Muscarinic M1/*antagonists & inhibitors
MH  - Receptor, Muscarinic M3/*antagonists & inhibitors
MH  - Young Adult
PMC - PMC3585954
EDAT- 2012/02/22 06:00
MHDA- 2012/07/24 06:00
PMCR- 2012/11/27
CRDT- 2012/02/21 06:00
PHST- 2012/02/21 06:00 [entrez]
PHST- 2012/02/22 06:00 [pubmed]
PHST- 2012/07/24 06:00 [medline]
PHST- 2012/11/27 00:00 [pmc-release]
AID - 12010017 [pii]
AID - 10.2165/11599330-000000000-00000 [doi]
PST - ppublish
SO  - Drugs R D. 2012 Mar 1;12(1):17-28. doi: 10.2165/11599330-000000000-00000.