吗啡剂量滴定用于慢性癌痛时吗啡及其代谢物的临床药代动力学

Clinical pharmacokinetics of morphine and its metabolites during morphine dose titration for chronic cancer pain.

作者信息

De Gregori Simona, Minella Cristina E, De Gregori Manuela, Tinelli Carmine, Ranzani Guglielmina N, Govoni Stefano, Allegri Massimo, Regazzi Mario

机构信息

†SIMPAR (Study In Multidisciplinary PAin Research) group, Unit of Clinical Pharmacokinetics in Transplantation and Autoimmune Disease, and Clinical Epidemiology and Biometric Unit, Fondazione IRCCS Policlinico San Matteo, and Department of Genetics and Microbiology, and Department of Experimental and Applied Pharmacology, University of Pavia; ‡Fondazione IRCCS Policlinico S. Matteo: Pain Therapy Service; §Fondazione IRCCS Policlinico S. Matteo; Departments of ¶Genetics and Microbiology II: Department of Experimental and Applied Pharmacology, ‖Drug Sciences, Pharmacology Section; and **Surgical, Clinical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.

出版信息

Ther Drug Monit. 2014 Jun;36(3):335-44. doi: 10.1097/FTD.0000000000000009.

DOI:10.1097/FTD.0000000000000009

PMID:24595069

Abstract

BACKGROUND

Pain is one of the most prevalent and distressing symptoms in patients with cancer. There is evidence from observational studies that many patients do not get adequate relief. Although data in the literature confirm the effectiveness of most opioid drugs for the treatment of chronic pain, there is limited information about opioid titration.

METHODS

The aim of this study was to evaluate the clinical pharmacokinetics of morphine (M) and their correlation with pharmacodynamic results (effective daily dose of M and side effects) during the M titration phase, in the management of chronic cancer pain. Fifty-two consecutive patients were administered Oramorph (Molteni Farmaceutici, Scandicci, Florence, Italy; beginning with 5 mg every 6 hours), to maintain pain intensity at low levels (visual analog scale <4). M, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) plasma concentrations were determined by a mass spectrometric assay.

RESULTS

Expected pharmacokinetic parameters were based on a pharmacokinetic profile extrapolated from 39 patients: M total clearance varied between 1.5 and 6.42 L·h(-1)·kg(-1); the median apparent volume of M distribution was 25.0 L/kg, and the elimination half-life was 4.4 hours. Over the entire period of treatment, a weak correlation between M and M3G or M6G concentrations was found, but the metabolite ratio (M3G/M6G) remained quite stable for each patient and at different sampling times. At the end of titration, the M6G/M ratio was significantly higher in the patients whose effective M concentration was below the median (5.2 ng/mL), than in patients in whom the concentration was above the median (M6G/M: 13.0 and 9.0, respectively).

CONCLUSIONS

This article presents the pharmacokinetic profiles of M and its metabolites: their concentration ratio could help clinicians to optimize individual therapies and tailor the dose to individual needs. Our results indicate that the relationship between M6G and M could represent a potentially useful parameter to personalize M dosing.

摘要

背景

疼痛是癌症患者中最普遍且令人痛苦的症状之一。观察性研究表明，许多患者并未得到充分缓解。尽管文献数据证实了大多数阿片类药物治疗慢性疼痛的有效性，但关于阿片类药物滴定的信息有限。

方法

本研究旨在评估在慢性癌痛管理的吗啡（M）滴定阶段，吗啡的临床药代动力学及其与药效学结果（M的有效日剂量和副作用）的相关性。连续52例患者服用奥施康定（莫尔泰尼制药公司，意大利佛罗伦萨斯坎迪奇；起始剂量为每6小时5毫克），以将疼痛强度维持在低水平（视觉模拟评分<4）。通过质谱分析法测定M、吗啡 - 3 - 葡萄糖醛酸苷（M3G）和吗啡 - 6 - 葡萄糖醛酸苷（M6G）的血浆浓度。

结果

预期药代动力学参数基于从39例患者推断出的药代动力学曲线：M的总清除率在1.5至6.42 L·h⁻¹·kg⁻¹之间变化；M分布的表观体积中位数为25.0 L/kg，消除半衰期为4.4小时。在整个治疗期间，发现M与M3G或M6G浓度之间存在弱相关性，但代谢物比率（M3G/M6G）在每位患者以及不同采样时间保持相当稳定。滴定结束时，有效M浓度低于中位数（5.2 ng/mL）的患者中M6G/M比率显著高于浓度高于中位数的患者（M6G/M分别为13.0和9.0）。