基于NONMEN模型建立的沙咪珠利在健康鸡及球虫感染鸡体内的群体药代动力学研究

There are some common problems of chicken coccidiosis in poultry farming industry, such as uncontrollable disease prevention, veterinary drug resistance, drug residues in animal derived food. The most effective way is to administrate continuous and mass concentration for anticoccidial drugs. The traditional detection of pharmacokinetics is by single dosing, and the number of sample animals is far lower than the actual that, so the measurement result of anticoccidial drug will have a large deviation which can not meet the demand of clinical drug administration. Ethanamizuril is a three triazine compound with high anticoccidial activity, low toxicity, no cross resistance, developed by our research team. In this study, it will be used by a population pharmacokinetic analysis method based on the traditional research with the increasing number of samples. With the physiological parameters and pathological parameters of chicken infected coccidiosis as covariates, mathematical modeling is established by NONMEN method in healthy chickens and coccidiosis-infected chickens to find the patterns of absorption and metabolism of Ethanamizuril in chickens, the relationship between the absorption and metabolic parameters and sample parameters of physiological and pathological parameters, finding the effects of covariates, and optimize the clinical drug administration. It is significant for new drugs to prevent disease, control coccidiosis drug resistant and reduce veterinary drug residues.

鸡球虫病作为家禽养殖业需面对的一个普遍问题，面临疾病防控不利，兽药耐药性，动物源性食品中药物残留超标等问题。防治鸡球虫病最有效的方式就是大批量集中连续给抗球虫药。在传统的药代动力学检测采用单次定量给药，样本数量远远小于实际给药的动物数，因此球虫药测定时的结果会与临床情况产生很大的偏差，不能满足指导临床用药的需求。沙咪珠利是本团队近年来开发的一种具有高抗球虫活性的新型三嗪类化合物，毒副作用低，无交叉耐药性。本研究在传统研究基础上采用群体药代动力学研究方法，通过大幅度增加样本数量，并将样本的生理参数及球虫病病理参数等作为协变量，通过NONMEN法进行数学建模，寻找沙咪珠利在健康鸡及球虫感染鸡的体内吸收代谢规律，挖掘各个吸收代谢参数与样本本身参数生理病理参数之间的相互关系，发现协变量的影响，从而指导优化群体给药方案。这对新药在球虫病防控以及延缓球虫耐药和降低兽药残留超标等方面将具有重大意义。

沙咪珠利是一种新型三嗪类化合物，在新型抗球虫治疗中具有潜在的应用前景。本研究建立了沙咪珠利在鸡血浆中的超高效液相串联质谱检测方法，并且进行了方法学验证，结果显示方法具有特异性，且准确度和精密度均符合检测要求。本研究建立了柔嫩艾美耳球虫的感染鸡模型，并且给予健康鸡和感染鸡口服沙咪珠利溶液，以2-4周龄鸡的的血药浓度为基础，建立了沙咪珠利的药动学模型。最终的模型表明，沙咪珠利在鸡体内呈一级吸收的二室模型分布。其表观清除率Cl和中心室分布Vc受年龄和体重的影响，中心室分布Vc及外周室分布Vp受体重和感染的影响。外部验证表明，该模型具有良好的预测精度和稳定性。本研究结果可以指导沙咪珠利的临床应用，发现沙咪珠利吸收代谢与动物本身的生理特征息息相关，球虫感染影响药代动力学行为。