Rationale, Development, and Validation of HdxSim, a Clinical Decision Support Tool for Model-Informed Precision Dosing of Hydroxyurea for Children with Sickle Cell Anemia.
Rationale, Development, and Validation of HdxSim, a Clinical Decision Support Tool for Model-Informed Precision Dosing of Hydroxyurea for Children with Sickle Cell Anemia.
复制标题
HdxSim 的基本原理、开发和验证，这是一种临床决策支持工具，用于为患有镰状细胞性贫血的儿童提供基于模型的羟基脲精确剂量。
DOI：
10.1002/cpt.3119
复制
发表时间：
2023
影响因子：
6.7
通讯作者：
Ware,RussellE
中科院分区：
文献类型：
--
作者：
Power-Hays,Alexandra;Dong,Min;Punt,Nieko;Mizuno,Tomoyuki;Smart,LukeR;Vinks,AlexanderA;Ware,RussellE
羟基脲治疗儿童镰状细胞性贫血（SCA）是有效的，可以挽救生命。逐步递增至最大耐受剂量（MTD）可提供最佳获益，但在逻辑上具有挑战性且耗时，尤其是在大多数SCA患者居住的低收入国家。与试错法剂量调整相比，羟基脲的模型通知精确给药（MIPD）加快了MTD的确定并改善了结局。HdxSim是一种用户友好的在线临床决策支持工具，旨在促进羟基脲MIPD，并使用真实的药代动力学（PK）数据进行评价。分析了两个临床试验数据集（长期效应的羟基脲研究（HUSTLE），NCT 00305175和治疗反应评价和依从性试验（TREAT），NCT 02286154）的首次给药羟基脲PK特征。将通过HdxSim估计的浓度-时间曲线下面积（AUC）与使用传统梯形方法和PK软件（MWPharm-DOS）测定的浓度-时间曲线下面积进行比较。将HdxSim和MWPharm-DOS预测的剂量与观察到的临床MTD进行比较。对于HUSTLE参与者，与梯形法相比，HdxSim准确估计了羟基脲AUC，方差< 20%。使用HdxSim（68.6 ± 18.0 mg* h/L）估计的TREAT受试者的平均（平均值± SD）AUC低于MWPharm-DOS（78.6 ± 20.7 mg* h/L，P= 0.012），但平均推荐剂量无差异（425 vs. 423 mg/d，P= 0.97）。此外，HdxSim在预测临床MTD方面非劣效于MWPharm-DOS（绝对差异3.9 ± 5.8 vs. 4.9 ± 8.2 mg/kg/天，P= 0.19）。HdxSim可准确估计羟基脲暴露量，在预测临床羟基脲MTD方面不劣于传统PK方法。基于目标暴露量的羟基脲给药可改善SCA儿童的结局，并有可能使全球这一被忽视的人群更容易获得PK指导的羟基脲给药。
Hydroxyurea treatment for children with sickle cell anemia (SCA) is effective and life‐saving. Stepwise escalation to maximum tolerated dose (MTD) provides optimal benefits, but is logistically challenging and time‐consuming, especially in low‐income countries where most people with SCA live. Model‐informed precision dosing (MIPD) of hydroxyurea expedites MTD determination and improves outcomes compared with trial‐and‐error dose adjustments. HdxSim, a user‐friendly, online, clinical decision support tool was developed to facilitate hydroxyurea MIPD and evaluated using real‐world pharmacokinetic (PK) data. First‐dose hydroxyurea PK profiles were analyzed from two clinical trial datasets (Hydroxyurea Study of Long‐Term Effects (HUSTLE), NCT00305175 and Therapeutic Response Evaluation and Adherence Trial (TREAT), NCT02286154). Areas under the concentration‐time curve (AUC) estimated by HdxSim were compared with those determined using traditional trapezoidal methodology and PK software (MWPharm‐DOS). The doses predicted by HdxSim and MWPharm‐DOS were compared with the observed clinical MTD. For HUSTLE participants, HdxSim accurately estimated hydroxyurea AUC compared with the trapezoidal method, with < 20% variance. The average (mean ± SD) AUC for TREAT participants estimated with HdxSim (68.6 ± 18.0 mg*hour/L) was lower than MWPharm‐DOS (78.6 ± 20.7 mg*hour/L,P= 0.012), but the average recommended doses were not different (425 vs. 423 mg/day,P= 0.97). Moreover, HdxSim was non‐inferior to MWPharm‐DOS at predicting clinical MTD (absolute difference 3.9 ± 5.8 vs. 4.9 ± 8.2 mg/kg/day,P= 0.19). HdxSim accurately estimates hydroxyurea exposure and is noninferior to traditional PK approaches at predicting the clinical hydroxyurea MTD. Hydroxyurea dosing based on target exposure leads to improved outcomes in children with SCA, and has the potential to make PK‐guided hydroxyurea dosing more accessible to this neglected population globally.
登录
查看更多内容
DOI：
10.2210/pdb3dfr/pdb
发表时间：
1982-11
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
J. Bolin;D. Filman;D. Matthews;R. Hamlin;J. Kraut
通讯作者：
J. Bolin;D. Filman;D. Matthews;R. Hamlin;J. Kraut
大肠杆菌二氢叶酸还原酶天冬氨酸 27 在活性和非活性酶构象异构体相互转化以及 NADPH 结合中的作用。
DOI：
--
发表时间：
1990
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Appleman,JR;Howell,EE;Kraut,J;Blakley,RL
通讯作者：
Blakley,RL
影响因子：
56.9
作者：
KRAUT, J
通讯作者：
KRAUT, J
影响因子：
56.9
作者：
HOWELL, EE;VILLAFRANCA, JE;KRAUT, J
通讯作者：
KRAUT, J
甲氨蝶呤和叶酸与二氢叶酸还原酶结合。
影响因子：
2.9
作者：
Y. Ozaki;R. King;P. Carey
通讯作者：
P. Carey