基于干血纸片法与定量药理学模型的哌拉西林/他唑巴坦在2个月以下患儿中的合理用药研究

细菌感染性疾病是造成婴儿死亡的主要原因之一。哌拉西林（有效成分）/他唑巴坦是治疗婴儿感染的常用复方制剂，但其在2个月以下婴儿患者中属于超说明书用药，合理给药方案有待明确。这主要是因为其在该人群中的临床PK/PD靶标和发育PK特征不明。另外，伦理学上采血量与采血次数的限制使得基于密集采样的传统PK/PD研究在婴儿中难以实施。本项目拟依托微量采血的干血纸片法与可处理稀疏血药浓度数据的定量药理学手段，设计微量采血的稀疏采样方案进行哌拉西林/他唑巴坦在2个月以下婴儿患者中的PK/PD研究，构建整合个体发育学特点的群体药动学模型阐明哌拉西林/他唑巴坦在婴儿患者中的PK特征，基于临床疗效与微生物学疗效数据构建药效学模型明确其PK/PD靶标，最后结合群体药动学模型与PK/PD靶标确定不同个体发育学特征婴儿患者的合理给药方案。本研究将为哌拉西林/他唑巴坦在2个月以下婴儿患者中的合理给药提供科学指导。

Bacterial infection is one of the main causes of infant death. Piperacillin (active ingredient)/tazobactam is a commonly used compound preparation for the treatment of infant infections, but it is currently used off-label and the rational dosing regimen needs to be clarified. This is because the clinical pharmacokinetics / pharmacodynamics (PK/PD) target and developmental PK of piperacillin/tazobactam are unknown in infants younger than 2 months. Additionally, the ethical limitations on the amount and frequency of blood collection make it difficult to implement traditional PK/PD studies in infants based on the intensive sampling. In this project, we intend to combine the dried blood spot method for micro-blood sampling and the pharmacometrics approach for handling sparse blood drug concentration data, and use these techniques to design a microsampling-based sparse blood sampling scheme for performing the PK/PD study of piperacillin/tazobactam in infants under 2 months, to construct an ontogeny mechanism-based population pharmacokinetic model for clarifying the PK characteristics of piperacillin/tazobactam in infants, and to build a pharmacodynamic model based on the clinical efficacy and microbiological efficacy data for determining its clinical PK/PD target, and finally to combine the population pharmacokinetic model and the PK/PD target for making rational dosing regimens in infants with different ontogeny characteristics. Through this project, we will provide scientific guidance for the rational dosing of piperacillin/tazobactam in infants under 2 months.