Department of Pediatric Hematology and Oncology, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Clinical Pharmacology - Hospital Pharmacy, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
Haemophilia. 2022 Jul;28(4):610-618. doi: 10.1111/hae.14575. Epub 2022 May 8.
To account for interindividual variability in the pharmacokinetics (PK) of factor concentrates, PK-guided dosing is increasingly implemented in haemophilia patients. Calculations are based on provided label potency, but legislation allows a potency difference of ±20% between label and actual potency. It is unknown if these differences affect PK guidance.
Explore the effects of potency differences on individual factor VIII (FVIII) PK parameters and the prediction of FVIII trough levels of dosing regimens.
We analyzed individual preoperative PK profiling data from severe and moderate haemophilia A patients included in the OPTI-CLOT randomized controlled trial. Label and actual potency were compared, with data on potency provided by pharmaceutical companies. For both potencies, individual PK parameters were estimated and concentration-time curves were constructed by nonlinear mixed-effects modelling. Finally, we explored the effect of both the identified and the maximum legislated potency difference on predicted FVIII trough levels infused in a low and high dose regimen.
In 45/50 included patients, actual potency was higher than its label potency. The median potency difference was 6.0% (range -9.2% to 18.4%) and resulted in varying individual PK parameter estimates but practically identical FVIII concentration-time curves. As expected, predicted FVIII trough levels were linearly correlated to the actual dose.
It is not necessary to take potency differences into account when applying PK guidance of FVIII concentrates in haemophilia A patients. However, when the patient is switched to another FVIII batch after PK-guided dosing, trough levels may deviate ±20% from calculations based on label dose.
为了考虑到因子浓缩物药代动力学（PK）的个体间变异性，PK 指导剂量越来越多地应用于血友病患者。计算基于提供的标签效价，但法规允许标签效价与实际效价之间存在±20%的差异。目前尚不清楚这些差异是否会影响 PK 指导。
探讨效价差异对个体凝血因子 VIII（FVIII）PK 参数的影响，以及对剂量方案 FVIII 谷浓度预测的影响。
我们分析了 OPTI-CLOT 随机对照试验中纳入的严重和中度血友病 A 患者的术前个体 PK 分析数据。比较了标签和实际效价，并由制药公司提供有关效价的数据。对于这两种效价，我们都估计了个体 PK 参数，并通过非线性混合效应模型构建了浓度-时间曲线。最后，我们探讨了已确定的和最大法定效价差异对低剂量和高剂量方案中预测的 FVIII 谷浓度输注的影响。
在纳入的 50 名患者中的 45 名中，实际效价高于其标签效价。效价差异的中位数为 6.0%（范围-9.2%至 18.4%），导致个体 PK 参数估计值不同，但 FVIII 浓度-时间曲线几乎相同。正如预期的那样，预测的 FVIII 谷浓度与实际剂量呈线性相关。
在应用血友病 A 患者的 FVIII 浓缩物 PK 指导剂量时，不需要考虑效价差异。然而，当患者在 PK 指导剂量后切换到另一个 FVIII 批次时，基于标签剂量计算的谷浓度可能会偏离±20%。
