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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.

Sun L, Ding L, Wang Y, Zhou W, Yan Z, Sun W, Zhang H, Ou N, Chen X - Drugs R D (2012)

Bottom Line: The pharmacokinetics and safety of BCQB in animals have been established in preclinical studies.No clinically significant change was noted in clinical laboratory parameters, cardiac parameters or vital signs.BCQB was safe and well tolerated in healthy Chinese subjects when administered intranasally with single and multiple doses across the doses studied.

View Article: PubMed Central - PubMed

Affiliation: China Pharmaceutical University, Nanjing, China.

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.

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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) AUCt; (b) AUC∞; (c) Cmax. Linear regression is shown in the figure. AUCt= AUC from time 0 to time t; AUC∞ = AUC from time 0 to infinity; Cmax = maximum concentration.
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Fig3: 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) AUCt; (b) AUC∞; (c) Cmax. Linear regression is shown in the figure. AUCt= AUC from time 0 to time t; AUC∞ = AUC from time 0 to infinity; Cmax = maximum concentration.

Mentions: The mean and SD values of Cmax, AUCt and AUC∞ versus dose relationships after single intranasal dosing of BCQB are presented in figure 3. Over the dose range studied, the mean Cmax, AUCt and AUC∞ increased linearly across the doses by linear regression analysis, with regression equations in figure 3. Dose proportionality was observed (p > 0.05) by the ANOVA on the values of ln(Cmax/dose) and ln(AUC/dose) among the three dose groups. Moreover, the mean slopes of the plots for ln(Cmax) or ln(AUC) versus ln(dose) were all close to 1, and the 90% CIs of the slopes were completely contained within the predefined range (0.500, 1.500) for dose proportionality. The mean slopes (90% CIs) were 1.067 (0.834, 1.300) for Cmax, 1.207 (0.921, 1.494) for AUCt, and 1.051 (0.762, 1.341) for AUC∞. Thus, Cmax and AUC proved to be dose proportional across the studied doses by different methods. The values of tmax, t1/2, CL/F and fe% were independent of dose (p > 0.05). There was no clinically significant pharmacokinetic difference (p > 0.05, by ITT) between males and females in the single-dose study.


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.

Sun L, Ding L, Wang Y, Zhou W, Yan Z, Sun W, Zhang H, Ou N, Chen X - Drugs R D (2012)

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) AUCt; (b) AUC∞; (c) Cmax. Linear regression is shown in the figure. AUCt= AUC from time 0 to time t; AUC∞ = AUC from time 0 to infinity; Cmax = maximum concentration.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585954&req=5

Fig3: 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) AUCt; (b) AUC∞; (c) Cmax. Linear regression is shown in the figure. AUCt= AUC from time 0 to time t; AUC∞ = AUC from time 0 to infinity; Cmax = maximum concentration.
Mentions: The mean and SD values of Cmax, AUCt and AUC∞ versus dose relationships after single intranasal dosing of BCQB are presented in figure 3. Over the dose range studied, the mean Cmax, AUCt and AUC∞ increased linearly across the doses by linear regression analysis, with regression equations in figure 3. Dose proportionality was observed (p > 0.05) by the ANOVA on the values of ln(Cmax/dose) and ln(AUC/dose) among the three dose groups. Moreover, the mean slopes of the plots for ln(Cmax) or ln(AUC) versus ln(dose) were all close to 1, and the 90% CIs of the slopes were completely contained within the predefined range (0.500, 1.500) for dose proportionality. The mean slopes (90% CIs) were 1.067 (0.834, 1.300) for Cmax, 1.207 (0.921, 1.494) for AUCt, and 1.051 (0.762, 1.341) for AUC∞. Thus, Cmax and AUC proved to be dose proportional across the studied doses by different methods. The values of tmax, t1/2, CL/F and fe% were independent of dose (p > 0.05). There was no clinically significant pharmacokinetic difference (p > 0.05, by ITT) between males and females in the single-dose study.

Bottom Line: The pharmacokinetics and safety of BCQB in animals have been established in preclinical studies.No clinically significant change was noted in clinical laboratory parameters, cardiac parameters or vital signs.BCQB was safe and well tolerated in healthy Chinese subjects when administered intranasally with single and multiple doses across the doses studied.

View Article: PubMed Central - PubMed

Affiliation: China Pharmaceutical University, Nanjing, China.

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.

Show MeSH
Related in: MedlinePlus