Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Center, Amsterdam, The Netherlands.
Department of Pharmacy, Uppsala University, Uppsala, Sweden.
CPT Pharmacometrics Syst Pharmacol. 2023 May;12(5):706-718. doi: 10.1002/psp4.12938. Epub 2023 Mar 25.
Publications on the exposure-effect relationships of factor concentrates for hemophilia treatment are limited, whereas such analyses give insight on treatment efficacy. Our objective was to examine the relationship between the dose, factor VIII (FVIII) levels and bleeding for rFVIII-SingleChain (lonoctocog alfa, Afstyla). Data from persons with severe hemophilia A on rFVIII-SingleChain prophylaxis from three clinical trials were combined. The published rFVIII-SingleChain population pharmacokinetic (PK) model was evaluated and expanded. The probability of bleeding was described with a parametric repeated time-to-event (RTTE) model. Data included 2080 bleeds, 2545 chromogenic stage assay, and 3052 one-stage assay FVIII levels from 241 persons (median age 19 years) followed for median 1090 days. The majority of the bleeds occurred in joints (65%) and the main bleeding reason was trauma (44%). The probability of bleeding decreased during follow-up and a FVIII level of 8.9 IU/dL (95% confidence interval: 6.9-10.9) decreased the bleeding hazard by 50% compared to a situation without FVIII in plasma. Variability in bleeding hazard between persons with similar FVIII levels was large, and the pre-study annual bleeding rate explained part of this variability. When a FVIII trough level of 1 or 3 IU/dL is targeted during prophylaxis, simulations predicted two (90% prediction interval [PI]: 0-17) or one (90% PI: 0-11) bleeds per year, respectively. In conclusion, the developed PK-RTTE model adequately described the relationship between dose, FVIII levels and bleeds for rFVIII-SingleChain. The obtained estimates were in agreement with those published for the FVIII concentrates BAY 81-8973 (octocog alfa) and BAY 94-9027 (damoctocog alfa pegol), indicating similar efficacy to reduce bleeding.
关于因子浓缩物治疗血友病的暴露-效应关系的出版物有限，而这些分析可以深入了解治疗效果。我们的目的是研究剂量、VIII 因子（FVIII）水平和出血之间的关系，以评估 rFVIII-SingleChain（lonoctocog alfa，Afstyla）。合并了三项临床试验中接受 rFVIII-SingleChain 预防治疗的严重血友病 A 患者的数据。评估并扩展了已发表的 rFVIII-SingleChain 群体药代动力学（PK）模型。采用参数重复时间至事件（RTTE）模型描述出血概率。数据包括 241 名患者的 2080 次出血、2545 次显色法测定和 3052 次一期法测定的 FVIII 水平，中位随访时间为 1090 天，患者年龄中位数为 19 岁。大多数出血发生在关节（65%），主要出血原因是创伤（44%）。随着随访时间的延长，出血风险降低，与血浆中没有 FVIII 的情况相比，FVIII 水平为 8.9 IU/dL（95%置信区间：6.9-10.9）可使出血风险降低 50%。FVIII 水平相似的患者之间出血风险的变异性较大，研究前的年出血率解释了这种变异性的一部分。当预防治疗的目标是 FVIII 谷值水平为 1 或 3 IU/dL 时，模拟预测每年分别有 2（90%预测区间[PI]：0-17）或 1（90%PI：0-11）次出血。总之，开发的 PK-RTTE 模型充分描述了 rFVIII-SingleChain 的剂量、FVIII 水平和出血之间的关系。所获得的估计值与 BAY 81-8973（octocog alfa）和 BAY 94-9027（damoctocog alfa pegol）FVIII 浓缩物的已发表估计值一致，表明疗效相似，可减少出血。
