Article: 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.Luning Sun, Li Ding, Yongqing Wang, Wenjia Zhou, Zhengyu Yan, Weilin Sun, Hongwen Zhang, Ning Ou, Xiaoping Chen[show abstract] [hide abstract]
ABSTRACT: 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. 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. 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. 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. 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.Drugs in R&D. 02/2012; 12(1):17-28.
Article: Determination of hydromorphone in human plasma by a sensitive RP-HPLC-ESI-MS method and its application to a clinical pharmacokinetic study in postoperative patients after low dose intravenous administration with infusion pump.[show abstract] [hide abstract]
ABSTRACT: A sensitive reverse phase high performance liquid chromatography-electrospray ionization-mass spectrometry (RP-HPLC-ESI-MS) method has been developed and validated for the determination of hydromorphone in human plasma using naloxone as the internal standard (IS). After alkalization with saturated sodium bicarbonate, the plasma samples were extracted with ethyl acetate. Chromatographic separation was performed on a C18 column with the column temperature of 50 °C and a mobile phase of 5mM ammonium acetate buffer containing 1% formic acid-methanol (88:12, v/v). Hydromorphone and the IS were detected by selected ion monitoring using the protonated molecules at m/z 286.2 for hydromorphone and m/z 328.2 for the IS. Calibration curve was linear over the range of 0.01-50 ng/mL. The lower limit of quantification was 0.01 ng/mL. The method was successfully applied to the pharmacokinetic study in postoperative patients after intravenous infusion of 1.5mg hydromorphone hydrochloride. The obtained main pharmacokinetic parameters of hydromorphone in postoperative patients were as follows: the maximum hydromorphone plasma concentration (C(max)) was (24.15 ± 12.51)ng/mL, the time to the C(max) was (10.0 ± 0.0)min, and the elimination half-life was (2.7 ± 0.8)h.Journal of pharmaceutical and biomedical analysis 11/2011; 61:15-21. · 2.45 Impact Factor
Article: Determination of bencycloquidium bromide in human urine using weak cation-exchange solid-phase extraction and LC-ESI-MS: Method validation and application to kinetic study of urinary excretion.Wenjia Zhou, Li Ding, Guili Xu, Yongqing Wang, Luning Sun, Jianchang He, Yao Huang, Linlin Hu, Xiaoping Chen[show abstract] [hide abstract]
ABSTRACT: A sensitive LC-ESI-MS method has been developed and validated for the determination of bencycloquidium bromide (BCQB) in human urine samples. The method utilized a solid-phase extraction (SPE) procedure, choosing carboxy propyl phase (CBA) as the extracting sorbent for purification of BCQB, with better baseline and higher selectivity achieved. Sample preparation by this method yielded very good and consistent mean recovery of above 94.5%. Another major benefit of the present method was the high detectability, with a lower limit of quantification (LLOQ) of 0.02ng/ml. The developed method was successfully applied to determine BCQB in human urine, and was proved to be suitable for use in Phase I clinical pharmacokinetic study of BCQB.Journal of pharmaceutical and biomedical analysis 04/2009; 50(1):35-40. · 2.45 Impact Factor
Article: Solid phase extraction and liquid chromatography-electrospray ionization-mass spectrometry for the determination of bencycloquidium bromide in human plasma.[show abstract] [hide abstract]
ABSTRACT: To support the clinical pharmacokinetic trials of bencycloquidium bromide (BCQB), a specific and sensitive method based on weak cation-exchange solid phase extraction (WCX-SPE) and HPLC-ESI-MS techniques for the determination of BCQB in human plasma was developed and validated. BCQB and the internal standard 1-ethyl-bencycloquidium bromide were separated on a Zorbax Eclipse Plus C18 column (3.5microm, 150mmx2.1mm i.d.) with a mobile phase consisted of 20mM ammonium acetate buffer solution containing 1% acetic acid (pH 3.6)-methanol (50:50, v/v), and the chromatographic run time for one sample was 8min. The lower limit of quantitation (LLOQ) of the method is 5pg/ml, which is critically important for the pharmacokinetic study of BCQB. The method possesses a reliable quantification range of 5-1000pg/ml, the acceptable intra- and inter-batch precision of less than 8.9%, and the extraction recovery of more than 90.6%. The method was successfully applied for the single-dose pharmacokinetic study of BCQB nasal spray in healthy Chinese volunteers.Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 03/2009; 877(10):897-901. · 2.78 Impact Factor