Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
Great Ormond Street Haemophilia Centre, Great Ormond Street Hospital for Children NHS Trust, London, UK.
Br J Clin Pharmacol. 2021 Nov;87(11):4408-4420. doi: 10.1111/bcp.14864. Epub 2021 May 4.
Population pharmacokinetic (PK) models are increasingly applied to perform individualized dosing of factor VIII (FVIII) concentrates in haemophilia A patients. To guarantee accurate performance of a population PK model in dose individualization, validation studies are of importance. However, external validation of population PK models requires independent data sets and is, therefore, seldomly performed. Therefore, this study aimed to validate a previously published population PK model for FVIII concentrates administrated perioperatively.
A previously published population PK model for FVIII concentrate during surgery was validated using independent data from 87 children with severe haemophilia A with a median (range) age of 2.6 years (0.03-15.2) and body weight of 14 kg (4-57). First, the predictive performance of the previous model was evaluated with MAP Bayesian analysis using NONMEM v7.4. Subsequently, the model parameters were (re)estimated using a combined dataset consisting of the previous modelling data and the data available for the external validation.
The previous model underpredicted the measured FVIII levels with a median of 0.17 IU mL . Combining the new, independent and original data, a dataset comprising 206 patients with a mean age of 7.8 years (0.03-77.6) and body weight of 30 kg (4-111) was obtained. Population PK modelling provided estimates for CL, V1, V2, and Q: 171 mL h 68 kg , 2930 mL 68 kg , 1810 mL 68 kg , and 172 mL h 68 kg , respectively. This model adequately described all collected FVIII levels, with a slight median overprediction of 0.02 IU mL .
This study emphasizes the importance of external validation of population PK models using real-life data.
群体药代动力学（PK）模型越来越多地应用于血友病 A 患者的因子 VIII（FVIII）浓缩物的个体化给药。为了保证群体 PK 模型在剂量个体化中的准确性能，验证研究至关重要。然而，群体 PK 模型的外部验证需要独立的数据集，因此很少进行。因此，本研究旨在验证先前发表的用于 FVIII 浓缩物围手术期给药的群体 PK 模型。
使用 87 名患有严重血友病 A 的儿童的独立数据（中位数（范围）年龄为 2.6 岁（0.03-15.2），体重为 14 公斤（4-57））验证先前发表的 FVIII 浓缩物手术期间群体 PK 模型。首先，使用 NONMEM v7.4 通过 MAP 贝叶斯分析评估先前模型的预测性能。随后，使用包含先前建模数据和外部验证可用数据的组合数据集重新估计模型参数。
先前的模型对测量的 FVIII 水平的预测偏低，中位数为 0.17 IU·mL。将新的、独立的和原始的数据相结合，获得了一个包含 206 名患者的数据集，平均年龄为 7.8 岁（0.03-77.6），体重为 30 公斤（4-111）。群体 PK 建模提供了 CL、V1、V2 和 Q 的估计值：171·mL·h·68·kg、2930·mL·68·kg、1810·mL·68·kg 和 172·mL·h·68·kg。该模型适当地描述了所有收集的 FVIII 水平，中位数略有偏高，为 0.02 IU·mL。
本研究强调了使用真实数据对群体 PK 模型进行外部验证的重要性。
