Chen Na, Yu Xuben, Li Lu, Yang Ping, Dong Rong, Huang Yizhen, Ling Xiao, Shentu Qiaoqiao, Yu Wenqiao, Jiang Saiping
Department of Clinical Pharmaceutical, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Hangzhou, People's Republic of China.
Infect Drug Resist. 2024 Sep 17;17:4055-4065. doi: 10.2147/IDR.S471918. eCollection 2024.
The population pharmacokinetics of nirmatrelvir/ritonavir (NIR/RIT) has not yet been described for critically ill adult patient.
This was a prospective observational population pharmacokinetic study of nirmatrelvir/ritonavir (NIR/RIT) in critically ill adult patients and identify optimal dosing regimens.
The prescription of NIR/RIT is determined by the attending physician and ranges from 150mg/100mg to 300mg/100mg twice a day. Two to three serial blood samples were collected for each patient after the second doses. We developed and validated PK model for plasma NIR and plasma RIT. Monte Carlo dosing simulations were performed to assess target attainment.
We analyzed 89 plasma samples from 31 adult patients. The data were best described by a one-compartment model. Among the covariates tested on pharmacokinetic parameters, creatinine clearance (CrCL) and area under curve (AUC) of RIT had a significant effect on apparent clearance (CL/F) of NIR. Mean (SD) parameters estimates for the absorption rate constant (Ka), apparent distribution (V/F) and CL/F were 0.42 (0.10) h. 36.5 (8.5) L, 3.6 (0.26) L/h, respectively. Dosing simulations showed that the target in vitro 90% effective concentration (EC) was more likely to be achieved twice a day than once a day at the same daily dose of NIR. High CrCL, low AUC of RIT were associated with a reduced likelihood of NIR reaching the target EC.
Based on our dosing simulations, the initial dosage of NIR/RIT was 300mg/100mg twice a day in critically ill patients with CrCL>45 mL/min; When CrCL in critically ill patients is between 15 and 45 mL/min, NIR/RIT is 150mg/100mg twice a day. The maintenance dose is adjusted according to CrCL and AUC of RIT, with the dosages varying between 75mg/100mg and 300mg/100mg.
对于重症成年患者，尚未描述奈玛特韦/利托那韦（NIR/RIT）的群体药代动力学。
这是一项针对重症成年患者的奈玛特韦/利托那韦（NIR/RIT）的前瞻性观察性群体药代动力学研究，并确定最佳给药方案。
NIR/RIT的处方由主治医师确定，范围为每日两次，每次150mg/100mg至300mg/100mg。在第二次给药后，为每位患者采集两到三份连续血样。我们建立并验证了血浆NIR和血浆RIT的药代动力学模型。进行蒙特卡洛给药模拟以评估目标达成情况。
我们分析了31名成年患者的89份血浆样本。数据用单室模型能得到最佳描述。在对药代动力学参数进行测试的协变量中，肌酐清除率（CrCL）和利托那韦的曲线下面积（AUC）对奈玛特韦的表观清除率（CL/F）有显著影响。吸收速率常数（Ka）、表观分布容积（V/F）和CL/F的平均（标准差）参数估计值分别为0.42（0.10）h、36.5（8.5）L、3.6（0.26）L/h。给药模拟表明，在相同每日剂量的奈玛特韦下，每日两次给药比每日一次给药更有可能达到体外90%有效浓度（EC）目标。高CrCL、低利托那韦AUC与奈玛特韦达到目标EC的可能性降低有关。
基于我们的给药模拟，对于CrCL>45 mL/min的重症患者，NIR/RIT的初始剂量为每日两次，每次300mg/100mg；当重症患者的CrCL在15至45 mL/min之间时，NIR/RIT为每日两次，每次150mg/100mg。维持剂量根据利托那韦的CrCL和AUC进行调整，剂量在75mg/100mg至300mg/100mg之间变化。
