化学药物临床药代动力学研究技术指导原则-2005

【H】GCL1-2指导原则编号：化学药物临床药代动力学研究技术指导原则二○○五年三月目录一、概述····················································································································································1二、药代动力学研究生物样品分析方法的建立和确证···············································2（一）常用分析方法·················································································································2（二）方法学确证······················································································································21、特异性······································································································································32、标准曲线和定量范围······································································································33、定量下限·································································································································44、精密度与准确度·················································································································45、样品稳定性···························································································································56、提取回收率··························································································································57、微生物学和免疫学分析·······························································································58、方法学质控··························································································································6（三）分析数据的记录与保存··························································································61、方法建立与确认的数据·······························································································72、样品分析的数据···············································································································73、其他相关信息·····················································································································7三、药代动力学研究的具体内容·····························································································7（一）健康志愿者药代动力学研究················································································81、单次给药药代动力学研究··························································································82、多次给药药代动力学研究·························································································113、进食对口服药物制剂药代动力学影响的研究···············································134、药物代谢产物的药代动力学研究··········································································145、药物-药物的药代动力学相互作用研究······························································14（二）目标适应症患者的药代动力学研究································································15（三）特殊人群药代动力学研究·····················································································151、肝功能损害患者的药代动力学研究····································································152、肾功能损害患者的药代动力学研究···································································163、老年人药代动力学研究······························································································174、儿科人群药代动力学研究··························································································17四、结语·················································································································································18五、参考文献······································································································································19六、著者·················································································································································20化学药物临床药代动力学研究技术指导原则一、概述新药的临床药代动力学研究旨在阐明药物在人体内的吸收、分布、代谢和排泄的动态变化规律。对药物上述处置过程的研究，是全面认识人体与药物间相互作用不可或缺的重要组成部分，也是临床制定合理用药方案的依据。在药物临床试验阶段，新药的临床药代动力学研究主要涉及如下内容：1、健康志愿者药代动力学研究包括单次给药的药代动力学研究、多次给药的药代动力学研究、进食对口服药物药代动力学影响的研究、药物代谢产物的药代动力学研究以及药物－药物的药代动力学相互作用研究。2、目标适应症患者的药代动力学研究3、特殊人群药代动力学研究包括肝功能损害患者的药代动力学研究、肾功能损害患者的药代动力学研究、老年患者的药代动力学研究和儿童患者的药代动力学研究。上述研究内容反映了新药临床药代动力学研究的基本要求。在新药研发实践中，可结合新药临床试验分期分阶段逐步实施，以期阐明临床实践所关注的该药药代动力学的基本特征，为临床合理用药奠定基础。鉴于不同类型药物的临床药代动力学特征各不相同，故应根据所研究品种的实际情况进行综合分析，确定不同阶段所拟研究的具体内容，合理设计试验方案，采用科学可行的试验技术，实施相关研究，并作出综合性1评价，为临床合理用药提供科学依据。二、药代动力学研究生物样品分析方法的建立和确证由于生物样品一般来自全血、血清、血浆、尿液或其他临床生物样品，具有取样量少、药物浓度低、干扰物质多（如激素、维生素、胆汁以及可能同服的其他药物）以及个体差异大等特点，因此必须根据待测物的结构、生物介质和预期的浓度范围，建立灵敏、专一、精确、可靠的生物样品定量分析方法，并对方法进行确证。（一）常用分析方法目前常用的分析方法有：（1）色谱法：气相色谱法(GC)、高效液相色谱法(HPLC)、色谱－质谱联用法（LC－MS、LC-MS-MS，GC-MS，GC-MS-MS）等，可用于大多数药物的检测；（2）免疫学方法：放射免疫分析法、酶免疫分析法、荧光免疫分析法等，多用于蛋白质多肽类物质检测；（3）微生物学方法，可用于抗生素药物的测定。从目前发展看，生物样品的分析一般首选色谱法，如HPLC、GC法或LC－MS、GC－MS法，这类方法灵敏度、特异性、准确性一般都能适应临床药代动力学研究的需要，多数实验室也具备条件，因此应用最广，大约90%的药物浓度测定可以用色谱法来完成。具体选用何种分析方法应根据药物的化学结构、理化性质、仪器条件以及借鉴文献方法多方面因素来考虑确定。（二）方法学确证建立可靠的和可重复的定量分析方法是进行临床药代动力学研究的关2键之一。为了保证分析方法可靠，必须对方法进行充分确证，一般应进行以下几方面的考察：1、特异性(Specificity)特异性是指在样品中存在干扰成分的情况下，分析方法能够准确、专一地测定分析物的能力。必须证明所测定物质是受试药品的原形药物或特定活性代谢物，生物样品所含内源性物质和相应代谢物、降解产物不得干扰对样品的测定，如果有几个分析物，应保证每一个分析物都不被干扰。应确定保证分析方法的最佳检测条件。对于色谱法至少要考察6个不同个体的空白生物样品色谱图、空白生物样品外加对照物质色谱图（注明浓度）及用药后