Abstract：
BACKGROUND: The use of intranasal dexmedetomidine is hampered by a limited understanding of its absorption pharmacokinetics.
METHODS: We examined the pharmacokinetics and feasibility of intranasal dexmedetomidine administered in the supine position to adult patients undergoing general anaesthesia. Twenty-eight patients between 35 and 80 years of age, ASA 1-3 and weight between 50 and 100 kg, who underwent elective unilateral total hip or knee arthroplasty under general anaesthesia were recruited. All patients received 100 μg of intranasal dexmedetomidine after anaesthesia induction. Six venous blood samples (at 0, 5, 15, 45, 60, 240 min timepoints from dexmedetomidine administration) were collected from each patient and dexmedetomidine plasma concentrations were measured. Concentration-time profiles after nasal administration were pooled with earlier data from a population analysis of intravenous dexmedetomidine (n = 202) in order to estimate absorption parameters using nonlinear mixed effects. Peak concentration (CMAX) and time (TMAX) were estimated using simulation (n = 1000) with parameter estimates and their associated variability.
RESULTS: There were 28 adult patients with a mean (SD) age of 66 (8) years and weight of 83 (10) kg. The mean weight-adjusted dose of dexmedetomidine was 1.22 (0.15) μg kg-1. CMAX 0.273 μg L-1 was achieved at 98 min after intranasal administration (TMAX). The relative bioavailability of dexmedetomidine was 80% (95% CI 75-91%). The absorption half-time (TABS = 120 min; 95% CI 90-147 min) was slower than that in previous pharmacokinetic studies on adult patients. Perioperative haemodynamics of all patients remained stable.
CONCLUSIONS: Administration of intranasal dexmedetomidine in the supine position during general anaesthesia is feasible with good bioavailability. This administration method has slower absorption when compared to awake patients in upright position, with consequent concentrations attained after TMAX for several hours.
METHODS: We examined the pharmacokinetics and feasibility of intranasal dexmedetomidine administered in the supine position to adult patients undergoing general anaesthesia. Twenty-eight patients between 35 and 80 years of age, ASA 1-3 and weight between 50 and 100 kg, who underwent elective unilateral total hip or knee arthroplasty under general anaesthesia were recruited. All patients received 100 μg of intranasal dexmedetomidine after anaesthesia induction. Six venous blood samples (at 0, 5, 15, 45, 60, 240 min timepoints from dexmedetomidine administration) were collected from each patient and dexmedetomidine plasma concentrations were measured. Concentration-time profiles after nasal administration were pooled with earlier data from a population analysis of intravenous dexmedetomidine (n = 202) in order to estimate absorption parameters using nonlinear mixed effects. Peak concentration (CMAX) and time (TMAX) were estimated using simulation (n = 1000) with parameter estimates and their associated variability.
RESULTS: There were 28 adult patients with a mean (SD) age of 66 (8) years and weight of 83 (10) kg. The mean weight-adjusted dose of dexmedetomidine was 1.22 (0.15) μg kg-1. CMAX 0.273 μg L-1 was achieved at 98 min after intranasal administration (TMAX). The relative bioavailability of dexmedetomidine was 80% (95% CI 75-91%). The absorption half-time (TABS = 120 min; 95% CI 90-147 min) was slower than that in previous pharmacokinetic studies on adult patients. Perioperative haemodynamics of all patients remained stable.
CONCLUSIONS: Administration of intranasal dexmedetomidine in the supine position during general anaesthesia is feasible with good bioavailability. This administration method has slower absorption when compared to awake patients in upright position, with consequent concentrations attained after TMAX for several hours.
摘要：
背景：鼻内右美托咪定的使用受到对其吸收药代动力学的有限理解的阻碍。
方法：我们研究了全身麻醉成年患者仰卧位鼻内右美托咪定的药代动力学和可行性。28名35至80岁的患者，ASA1-3，体重在50到100公斤之间，我们招募了在全身麻醉下进行择期单侧全髋关节或膝关节置换术的患者.所有患者在麻醉诱导后鼻内给予100μg右美托咪定。从每个患者收集6个静脉血样品(在从右美托咪定施用的0、5、15、45、60、240分钟时间点),并测量右美托咪定血浆浓度。将鼻给药后的浓度-时间曲线与来自静脉内右美托咪定(n=202)的群体分析的早期数据合并,以便使用非线性混合效应来估计吸收参数。使用具有参数估计及其相关变异性的模拟(n=1000)来估计峰值浓度(CMAX)和时间(TMAX)。
结果：有28名成年患者，平均（SD）年龄为66（8）岁，体重为83（10）kg。右美托咪定的平均体重调整剂量为1.22(0.15)μgkg-1。在鼻内给药(TMAX)后98分钟达到CMAX0.273μgL-1。右美托咪定的相对生物利用度为80%(95%CI75-91%)。吸收半衰期（TABS=120分钟；95％CI90-147分钟）比先前对成年患者的药代动力学研究慢。所有患者围手术期血流动力学均保持稳定。
结论：全身麻醉期间仰卧位鼻内给药右美托咪定是可行的，生物利用度良好。与直立的清醒患者相比，这种给药方法吸收较慢，在TMAX持续数小时后达到浓度。
方法：我们研究了全身麻醉成年患者仰卧位鼻内右美托咪定的药代动力学和可行性。28名35至80岁的患者，ASA1-3，体重在50到100公斤之间，我们招募了在全身麻醉下进行择期单侧全髋关节或膝关节置换术的患者.所有患者在麻醉诱导后鼻内给予100μg右美托咪定。从每个患者收集6个静脉血样品(在从右美托咪定施用的0、5、15、45、60、240分钟时间点),并测量右美托咪定血浆浓度。将鼻给药后的浓度-时间曲线与来自静脉内右美托咪定(n=202)的群体分析的早期数据合并,以便使用非线性混合效应来估计吸收参数。使用具有参数估计及其相关变异性的模拟(n=1000)来估计峰值浓度(CMAX)和时间(TMAX)。
结果：有28名成年患者，平均（SD）年龄为66（8）岁，体重为83（10）kg。右美托咪定的平均体重调整剂量为1.22(0.15)μgkg-1。在鼻内给药(TMAX)后98分钟达到CMAX0.273μgL-1。右美托咪定的相对生物利用度为80%(95%CI75-91%)。吸收半衰期（TABS=120分钟；95％CI90-147分钟）比先前对成年患者的药代动力学研究慢。所有患者围手术期血流动力学均保持稳定。
结论：全身麻醉期间仰卧位鼻内给药右美托咪定是可行的，生物利用度良好。与直立的清醒患者相比，这种给药方法吸收较慢，在TMAX持续数小时后达到浓度。
