1LAP&P Consultants BV, Leiden, the Netherlands.
Clin Appl Thromb Hemost. 2014 May;20(4):355-64. doi: 10.1177/1076029613516188. Epub 2013 Dec 11.
Population pharmacokinetic (PK) analyses were conducted to refine dosing recommendations for recombinant human anti-thrombin therapy in surgery and delivery patients with hereditary antithrombin deficiency (HD). Single-dose PK data from patients with HD and nonlinear mixed-effects modeling were used to devise a dosing regimen to target antithrombin (AT) activity levels between 80% and 120% of normal. External validation with data from a phase 3 trial confirmed the correctness of a covariate-free model for surgery patients, but dosing adjustment was necessary for delivery patients. After different covariates were tested, the model was updated to incorporate the influential covariate, delivery. Simulations were used to develop a therapeutic drug-monitoring scenario that results in steady state AT activity levels within the target range as quickly as practically feasible. Data from a second clinical trial provided additional external validation and confirmed the accuracy of the dosing model for both groups of patients.
进行了群体药代动力学（PK）分析，以改进遗传性抗凝血酶缺陷（HD）手术和分娩患者中重组人抗凝血酶治疗的给药建议。使用 HD 患者的单剂量 PK 数据和非线性混合效应模型来设计一种给药方案，以将抗凝血酶（AT）活性水平靶向至正常水平的 80%至 120%。来自 3 期临床试验的数据的外部验证证实了手术患者无协变量模型的正确性，但需要对分娩患者进行剂量调整。在测试了不同的协变量后，该模型进行了更新以纳入有影响的协变量——分娩。模拟用于开发治疗药物监测方案，使稳态 AT 活性水平尽快达到目标范围内，在实际可行的范围内。来自第二项临床试验的数据提供了额外的外部验证，并证实了该给药模型对两组患者的准确性。
