Abstract：
Morphine and morphine-6-glucuronide (M6G) produce central nervous system (CNS) effects by activating mu-opioid receptors, while naloxone is used mainly for the reversal of opioid overdose, specifically for the fatal complication of respiratory depression, but also for alleviating opioid-induced side effects. In this study we developed a physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model to simultaneously predict pharmacokinetics and CNS effects (miosis, respiratory depression and analgesia) of morphine as well as antagonistic effects of naloxone against morphine. The pharmacokinetic and pharmacodynamic parameters were obtained from in vitro data, in silico, or animals. Pharmacokinetic and pharmacodynamic simulations were conducted using 39 and 36 clinical reports, respectively. The pharmacokinetics of morphine and M6G following oral or intravenous administration were simulated, and the PBPK-PD model was validated using clinical observations. The Emax model correlated CNS effects with free concentrations of morphine and M6G in brain parenchyma. The predicted CNS effects were compared with observations. Most clinical observations fell within the 5th-95th percentiles of simulations based on 1000 virtual individuals. Most of the simulated area under the concentration-time curve or peak concentrations also fell within 0.5-2-fold of observations. The contribution of morphine to CNS effects following intravenous or oral administration was larger than that of M6G. Pharmacokinetics and antagonistic effects of naloxone on CNS effects were also successfully predicted using the developed PBPK-PD model. In conclusion, the pharmacokinetics and pharmacodynamics of morphine and M6G, antagonistic effects of naloxone against morphine-induced CNS effects may be successfully predicted using the developed PBPK-PD model based on the parameters derived from in vitro, in silico, or animal studies.
摘要：
吗啡和吗啡-6-葡糖苷酸（M6G）通过激活μ阿片受体产生中枢神经系统（CNS）作用，虽然纳洛酮主要用于逆转阿片类药物过量，特别是针对呼吸抑制的致命并发症，而且还可以减轻阿片类药物引起的副作用。在这项研究中，我们开发了基于生理的药代动力学-药效学（PBPK-PD）模型，以同时预测药代动力学和CNS作用（瞳孔缩小，呼吸抑制和镇痛）吗啡以及纳洛酮对吗啡的拮抗作用。从体外数据获得药代动力学和药效学参数，在硅，或动物。使用39和36份临床报告进行药代动力学和药效学模拟，分别。吗啡和M6G口服或静脉给药后的药代动力学模拟，PBPK-PD模型通过临床观察得到验证。Emax模型将CNS作用与脑实质中吗啡和M6G的游离浓度相关联。将预测的CNS作用与观察结果进行比较。大多数临床观察结果都落在基于1000个虚拟个体的模拟的第5-95百分位数之内。浓度-时间曲线下的大多数模拟面积或峰浓度也落在观测值的0.5-2倍之内。静脉内或口服后吗啡对CNS作用的贡献大于M6G。使用开发的PBPK-PD模型也成功预测了纳洛酮对CNS作用的药代动力学和拮抗作用。总之,吗啡和M6G的药代动力学和药效学，纳洛酮对吗啡诱导的中枢神经系统效应的拮抗作用可以使用开发的PBPK-PD模型成功预测，基于来自体外的参数，在硅，或动物研究。
