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(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 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 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.

Fig. 1

Chemical structure of bencycloquidium bromide.

Table I

Summary of baseline demographics^a

Table II

Study design

Fig. 2

Mean plasma (a) and log-scaled mean plasma (b) concentration-time profiles of bencycloquidium bromide following single intranasal doses in healthy Chinese subjects. The inset expands the first 3 hours of the profile. Data are presented as mean + SD (n = 10 per dose). LLOQ = lower limit of quantitation.

Table III

Main pharmacokinetic parameters of bencycloquidium bromide in healthy Chinese subjects after single intranasal doses 45, 90, and 180 μg^a

Fig. 3

Mean value (± SD) dose profiles of bencycloquidium bromide (BCQB) following single intranasal doses of BCQB 45, 90, and 180 μg (n = 10 per dose). (a) AUC_t; (b) AUC_∞; (c) C_max. Linear regression is shown in the figure. AUC _t = AUC from time 0 to time t; AUC _∞ = AUC from time 0 to infinity; C _max = maximum concentration.

Fig. 4

Mean plasma concentration-time profiles of bencycloquidium bromide on day 1 and day 7 following multiple intranasal doses in healthy Chinese subjects, respectively. The inset expands the first 3 hours of the profile. Data are presented as mean ± SD (n = 10 per dose).

Table IV

Main pharmacokinetic parameters of bencycloquidium bromide in healthy Chinese subjects after multiple intranasal administration of 120 μg, with single administration on day 1; received no treatment on day 2; and continued to receive the study drug three times daily from days 3 through 7^a

Table V

Treatment-emergent adverse events occurring in two or more subjects (safety population, n = 58)