The phenylephrine concentration-response relationship for blood pressure after nasal delivery in children
The phenylephrine concentration-response relationship for blood pressure after nasal delivery in children
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DOI：
10.1111/pan.13221
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发表时间：
2017-10-01
影响因子：
1.7
通讯作者：
Friesen, Robert H.
中科院分区：
文献类型：
--
作者：
Anderson, Brian J.;Christensen, Lisa K.;Friesen, Robert H.
背景资料：鼻内苯乙哌啶通常用于收缩鼻粘膜血管，减少鼻气管插管或内窥镜鼻窦手术相关出血。有几个数据量化无论是吸收药代动力学或苯肾上腺素浓度对儿童血压的影响。已发表的苯乙哌啶鼻腔给药后血浆浓度和血压变化的观察结果（0.1 mL/kg（-1）、0.25%或0.5%），儿童（n = 52，2 - 12岁，10 - 40 kg）与给予苯异丙胺2.5%（n = 10）和10%（n = 10）滴眼液的成人（23 - 81岁）合并。进一步的药代动力学（PK）数据可从单独口服苯乙哌啶10 mg的健康志愿者获得，在5、15、30、45分钟和1、2、3、6小时（n = 28）采集血液进行浓度测定。静脉注射时间-浓度数据来自4名健康志愿者，他们接受了苯丙氨酸1 mg给药，并在随后的4小时内17次采血进行分析。采用非线性混合效应模型，采用药代动力学-药效学（PK-PD）综合模型分析数据。将异速生长（按比例缩放至70 kg的人）用于PK大小标准化。结果：采用二室模型拟合药代动力学数据，用平衡半衰期（T（1/2）keo）关联的二室模型描述药代动力学效应。鼻用制剂的PK参数估计值为清除率（CL）160 L h（-1）、中心分布容积（V1）13.3 L、室间清除率（Q）25.3 L h（-1）、外周分布容积（V2）225 L、吸收半衰期（Tabs）6.2分钟、吸收滞后时间（Tlag）1.5分钟和生物利用度（F）0.183。滴眼液的生物利用度和吸收具有浓度依赖性（2.5%溶液的F 0.13，Tabs 5.5分钟; 10%溶液的F 0.15，Tabs 9.6分钟）。口服制剂吸收缓慢（Tabs 48分钟），生物利用度较差（F 0.0128）。儿科PD询问显示基线平均动脉压为60 mm Hg，最大效应（E-MAX）为25 mm Hg，EC50为10.3 μ g L-1。结论：苯乙奎醚经鼻粘膜吸收迅速，与眼用制剂吸收相似。生物利用度也与眼用制剂相似。儿童的最大效应（E-MAX）是成人的一半（E-MAX 50 mm Hg）。
Background: Intranasal phenylephrine is commonly used to vasoconstrict the nasal mucosa, reducing bleeding associated with nasotracheal intubation or endoscopic sinus surgery. There are few data quantifying either absorption pharmacokinetics or phenylephrine concentration effect on blood pressure in children.Methods: Published observations of plasma concentration and blood pressure changes after phenylephrine nasal administration (0.1 mL kg(-1), 0.25% or 0.5%) in children (n = 52, 2-12 years, 10-40 kg) were pooled with those in adults (23-81 years) given phenylephrine 2.5% (n = 10) and 10% (n = 10) eyedrops. Further pharmacokinetic (PK) data were available from healthy volunteers given oral phenylephrine 10 mg alone, with blood for concentration assay taken at 5, 15, 30, 45 minutes and 1, 2, 3, 6 hours (n = 28). Intravenous time-concentration data were available from four healthy volunteers given phenylephrine 1 mg and who had blood taken for assay on 17 occasions over the subsequent 4 hours. Data were analyzed using an integrated pharmacokinetic-pharmacodynamic (PK-PD) model using nonlinear mixed-effects models. Allometry, scaled to a 70-kg person, was used for PK size standardization. Effect was described using an E-MAX model.Results: A two-compartment model was used to fit PK data while an additional compartment, linked by an equilibration half-time (T(1/2)keo), was used to describe effect. PK parameter estimates for the nasal formulation were clearance (CL) 160 L h(-1), central volume of distribution (V1) 13.3 L, intercompartment clearance (Q) 25.3 L h(-1), peripheral volume of distribution (V2) 225 L, absorption half-time (Tabs) 6.2 minutes, absorption lag time (Tlag) 1.5 minutes, and bioavailability (F) 0.183. Bioavailability and absorption of the ophthalmic solution were concentration dependent (F 0.13, Tabs 5.5 minutes for 2.5% solution; F 0.15, Tabs 9.6 minutes for 10% solution). Absorption of the oral formulation was slow (Tabs 48 minutes) with poor bioavailability (F 0.0128). The pediatric PD interrogation revealed a baseline mean arterial pressure of 60 mm Hg, a maximum effect (E-MAX) of 25 mm Hg, and an EC50 of 10.3 mu g L-1. The effect on vasculature was immediate and T(1/2)keo was not estimable.Conclusion: Absorption of phenylephrine through the nasal mucosa was rapid and similar to the ophthalmic formulation. Bioavailability was also similar to the ophthalmic formulation. The maximum effect (E-MAX) in children was half that in adults (E-MAX 50 mm Hg).