Pharmacokinetic–Pharmacodynamic Modelling in Hemophilia A: Relating Thrombin and Plasmin Generation to Factor VIII Activity After Administration of a VWF/FVIII Concentrate,European Journal of Drug Metabolism and Pharmacokinetics

当前位置： X-MOL 学术 › Eur J Drug Metab Pharmacokinet › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Pharmacokinetic–Pharmacodynamic Modelling in Hemophilia A: Relating Thrombin and Plasmin Generation to Factor VIII Activity After Administration of a VWF/FVIII Concentrate
European Journal of Drug Metabolism and Pharmacokinetics ( IF 1.9 ) Pub Date : 2024-02-17 , DOI: 10.1007/s13318-024-00876-6
Lars L F G Valke _{1,

2} , Michael E Cloesmeijer ₃ , Hassan Mansouritorghabeh ₄ , Wideke Barteling ₅ , Nicole M A Blijlevens ₁ , Marjon H Cnossen ₆ , Ron A A Mathôt ₃ , Saskia E M Schols _{1,

2} , Waander L van Heerde _{1,

2,

7}

Affiliation

Background

Hemophilia A patients are treated with factor (F) VIII prophylactically to prevent bleeding. In general, dosage and frequency are based on pharmacokinetic measurements. Ideally, an alternative dose adjustment can be based on the hemostatic potential, measured with a thrombin generation assay (TGA), like the Nijmegen hemostasis assay.

Objective

The objective of this study was to investigate the predicted performance of a previously developed pharmacokinetic–pharmacodynamic model for FVIII replacement therapy, relating FVIII dose and FVIII activity levels with thrombin and plasmin generation parameters.

Methods

Pharmacokinetic and pharmacodynamic measurements were obtained from 29 severe hemophilia A patients treated with pdVWF/FVIII concentrate (Haemate P^®). The predictive performance of the previously developed pharmacokinetic–pharmacodynamic model was evaluated using nonlinear mixed-effects modeling (NONMEM). When predictions of FVIII activity or TGA parameters were inadequate [median prediction error (MPE) > 20%], a new model was developed.

Results

The original pharmacokinetic model underestimated clearance and was refined based on a two-compartment model. The pharmacodynamic model displays no bias in the observed normalized thrombin peak height and normalized thrombin potential (MPE of 6.83% and 7.46%). After re-estimating pharmacodynamic parameters, EC₅₀ and E_max values were relatively comparable between the original model and this group. Prediction of normalized plasmin peak height was inaccurate (MPE 58.9%).

Conclusion

Our predictive performance displayed adequate thrombin pharmacodynamic predictions of the original model, but a new pharmacokinetic model was required. The pharmacodynamic model is not factor specific and applicable to multiple factor concentrates. A prospective study is needed to validate the impact of the FVIII dosing pharmacodynamic model on bleeding reduction in patients.

中文翻译：

A 型血友病的药代动力学-药效学模型：施用 VWF/FVIII 浓缩物后将凝血酶和纤溶酶的生成与因子 VIII 活性联系起来

背景

A 型血友病患者采用因子 (F) VIII 进行预防性治疗，以防止出血。一般来说，剂量和频率基于药代动力学测量。理想情况下，替代剂量调整可以基于使用凝血酶生成测定（TGA）（如奈梅亨止血测定）测量的止血潜力。

客观的

本研究的目的是调查先前开发的 FVIII 替代疗法的药代动力学-药效学模型的预测性能，将 FVIII 剂量和 FVIII 活性水平与凝血酶和纤溶酶生成参数联系起来。

方法

对 29 名接受 pdVWF/FVIII 浓缩物 (Haemate P ^® ) 治疗的严重 A 型血友病患者进行了药代动力学和药效学测量。使用非线性混合效应模型（NONMEM）评估先前开发的药代动力学-药效模型的预测性能。当 FVIII 活性或 TGA 参数的预测不充分时 [中位预测误差 (MPE) > 20%]，开发了一种新模型。

结果

最初的药代动力学模型低估了清除率，并根据二室模型进行了改进。药效模型显示观察到的标准化凝血酶峰高和标准化凝血酶电位（MPE 分别为 6.83% 和 7.46%）没有偏差。重新估计药效参数后，原始模型与该组之间的EC ₅₀和E _max值具有相对可比性。标准化纤溶酶峰高的预测不准确（MPE 58.9%）。