Xie Helin, Zheng You, Zhang Hui, Guo Yanmei, Liu Maobai, Weng Qinyong, Wu Xuemei
Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, People's Republic of China.
College of Pharmacy, Fujian Medical University, Fuzhou, Fujian, 350000, People's Republic of China.
Drug Des Devel Ther. 2025 Mar 4;19:1527-1541. doi: 10.2147/DDDT.S495647. eCollection 2025.
Significant variability in the metabolism of midazolam (MDZ) exists among mechanically ventilated (MV) patients in the intensive care unit (ICU) due to complex clinical conditions and genetic factors. The NR1I2 gene (PXR), which encodes a nuclear receptor that regulates drug-metabolizing enzymes like CYP3A4, plays a critical role in MDZ metabolism. Polymorphisms in NR1I2, along with variations in genes such as CYP3A4, CYP3A5, and ABCB1, may influence enzyme activity and MDZ pharmacokinetics (PK). Understanding these factors is essential for optimizing MDZ dosing in high-risk patient populations.
We studied 61 MV ICU patients receiving continuous MDZ infusion. A population pharmacokinetic (PopPK) model was used to assess MDZ PK, with genetic factors (NR1I2 rs2461817, CYP3A4, CYP3A5, ABCB1, and other PXR polymorphisms) and clinical covariates (body weight (BW), aspartate aminotransferase (AST) levels) evaluated for their impact on MDZ clearance (CL).
The PK of MDZ and its metabolite, 1-hydroxymidazolam (1-OH-MDZ), were accurately described using a one-compartment model. The estimated population means for MDZ and 1-OH-MDZ CL were 22.6 L/h (inter-individual variability [IIV] 59.4%) and 67.1 L/h (IIV 57.7%), respectively. MDZ CL was significantly associated with the NR1I2 rs2461817 polymorphism and AST levels, accounting for 11.3% of the variability. MDZ CL decreased by 32.7% as AST increased from 22 IU/L to 60 IU/L, and by 40.7% in patients homozygous for the NR1I2 rs2461817 variant. BW also influenced the CL of 1-OH-MDZ, demonstrating a 34.2% increase as weight increased from 54 kg to 65 kg. Simulations confirmed the significant impact of NR1I2 rs2461817 on MDZ CL.
The PopPK model highlights the significant impact of NR1I2 rs2461817 polymorphism on MDZ CL in Chinese MV patients, emphasizing the need to consider genetic and clinical factors for optimizing MDZ dosing in ICU settings.
由于复杂的临床状况和遗传因素，重症监护病房（ICU）中机械通气（MV）患者的咪达唑仑（MDZ）代谢存在显著差异。NR1I2基因（PXR）编码一种核受体，该受体调节诸如CYP3A4等药物代谢酶，在MDZ代谢中起关键作用。NR1I2基因多态性以及CYP3A4、CYP3A5和ABCB1等基因的变异可能影响酶活性和MDZ的药代动力学（PK）。了解这些因素对于优化高危患者群体的MDZ给药至关重要。
我们研究了61例接受MDZ持续输注的MV ICU患者。使用群体药代动力学（PopPK）模型评估MDZ的PK，评估遗传因素（NR1I2 rs2461817、CYP3A4、CYP3A5、ABCB1以及其他PXR多态性）和临床协变量（体重（BW）、天冬氨酸转氨酶（AST）水平）对MDZ清除率（CL）的影响。
使用单室模型准确描述了MDZ及其代谢产物1-羟基咪达唑仑（1-OH-MDZ）的PK。MDZ和1-OH-MDZ CL的估计群体均值分别为22.6 L/h（个体间变异性[IIV]为59.4%）和67.1 L/h（IIV为57.7%）。MDZ CL与NR1I2 rs2461817多态性和AST水平显著相关，占变异性的11.3%。随着AST从22 IU/L增加到60 IU/L，MDZ CL降低32.7%，在NR1I2 rs2461817变异纯合子患者中降低40.7%。BW也影响1-OH-MDZ的CL，体重从54 kg增加到65 kg时，CL增加34.2%。模拟结果证实了NR1I2 rs2461817对MDZ CL的显著影响。
PopPK模型突出了NR1I2 rs2461817多态性对中国MV患者MDZ CL的显著影响，强调在ICU环境中优化MDZ给药时需要考虑遗传和临床因素。
