Brokjær Anne, Kreilgaard Mads, Olesen Anne Estrup, Simonsson Ulrika S H, Christrup Lona Louring, Dahan Albert, Drewes Asbjørn Mohr
Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark.
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Eur J Pharm Sci. 2015 Feb 20;68:78-86. doi: 10.1016/j.ejps.2014.12.004. Epub 2014 Dec 5.
To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: (1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), (2) to simulate clinically relevant rectal doses of morphine and (3) to assess the tolerability and safety.
This open label, dose escalation, four-sequence study was conducted in 10 healthy males. Three escalating doses of morphine hydrochloride (10mg, 15 mg and 20 mg) were administered 20 cm from the anal verge. A 2mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained by centrifugation and assayed for contents of morphine and M6G with a validated high performance liquid chromatographic method. Modelling was performed using NONMEM 7.2 and the first order conditional estimation method with interaction.
A two compartment distribution model with one absorption transit compartment for rectal administration and systemic clearance from the central compartment best described data. Systemic PK parameters were allometric scaled with body weight. The mean morphine absorption transit time was 0.6h, clearance 78 L/h [relative standard error (RSE) 12%] and absolute bioavailability 24% (RSE 11%). To obtain clinically relevant serum concentrations, simulations revealed that a single morphine hydrochloride dose of 35 mg will provide sufficient peak serum concentration levels and a 46 mg dose four times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was suggested to be an important covariate for morphine exposure. No severe side effects were observed.
A population pharmacokinetic model of liquid rectal morphine and M6G was developed. The model can be used to simulate rectal doses to maintain analgesic activity in the clinic. The studied doses were safe and well tolerated.
为了通过直肠途径安全有效地给予液体制剂吗啡，有必要全面了解其药代动力学。目的如下：（1）建立液体制剂直肠吗啡和吗啡 - 6 - 葡萄糖醛酸苷（M6G）的群体药代动力学模型；（2）模拟临床上相关的直肠吗啡剂量；（3）评估耐受性和安全性。
本开放标签、剂量递增、四序列研究纳入了10名健康男性。在距肛门边缘20厘米处给予三种递增剂量的盐酸吗啡（10毫克、15毫克和20毫克）。静脉注射2毫克盐酸吗啡作为对照。在基线和给药后九个时间点采集血样。通过离心获得血清，并用经过验证的高效液相色谱法测定吗啡和M6G含量。使用NONMEM 7.2和带有交互作用的一阶条件估计法进行建模。
一个具有直肠给药吸收转运室和中央室全身清除的二室分布模型能最好地描述数据。全身药代动力学参数与体重呈异速生长比例关系。吗啡的平均吸收转运时间为0.6小时，清除率为78升/小时[相对标准误差（RSE）为12%]，绝对生物利用度为24%（RSE为11%）。为获得临床上相关的血清浓度，模拟结果显示，单次35毫克盐酸吗啡剂量将提供足够的血清峰浓度水平，建议每日四次给予46毫克剂量以维持临床上相关的稳态浓度。体重被认为是影响吗啡暴露的一个重要协变量。未观察到严重副作用。
建立了液体制剂直肠吗啡和M6G的群体药代动力学模型。该模型可用于模拟直肠剂量以维持临床镇痛活性。所研究的剂量安全且耐受性良好。
