Morfini Massimo, Peyvandi Flora, Mancuso Maria Elisa, Marchesini Emanuela, Tagliaferri Annarita, Gualtierotti Roberta, Castaman Giancarlo, Pollio Berardino, Santoro Cristina, Banov Luisa, Napolitano Mariasanta, Preti Paola Stefania, Santoro Rita Carlotta, Coppola Antonio, Linari Silvia, Santagostino Elena, Bernardi Francesco
Italian Association of Hemophilia Centers (AICE), I 20120 Milan, Italy.
Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCSS Ca' Granda Maggiore Hospital, "Angelo Bianchi Bonomi", I 20120 Milan, Italy.
J Clin Med. 2024 Aug 23;13(17):4986. doi: 10.3390/jcm13174986.
A compartmental pharmacokinetics (PK) analysis of new extended half-life FVIII concentrates has never been performed in a large cohort of hemophilia patients. An improved PK analysis of individual outcomes may help to tailor hemophilia replacement treatment. PK outcomes after the infusion of a standard single dose of Efmoroctocog alfa were collected from 173 patients with severe/moderately severe hemophilia A in 11 Italian hemophilia centers. Factor VIII clotting activity (FVIII:C) was measured by one-stage clotting assay (OSA) in all patients, and chromogenic substrate assay (CSA) in a subgroup ( = 52). Fifty patients underwent a comparative PK assessment with standard half-life (SHL) recombinant FVIII (rFVIII) products. Non-compartmental analysis (NCA), one compartment model (OCM), and TCM were used to analyze the decay curves of all patients, and one-way paired ANOVA to compare the PK outcomes. All 173 PKs conformed to the NCA and OCM, but only 106 (61%) conformed to the TCM based on the biphasic features of their decay curves. According to the TCM, the Beta HL and MRT of rFVIIIFc were 20.42 ± 7.73 and 25.64 ± 7.61 h, respectively. ANOVA analysis of the outcomes from the three PK models showed significant differences in clearance, half-life (HL), and mean residence time (MRT) ( < 0.001 for all parameters). As anticipated, the HL and MRT of rFVIIIFc were longer than those of SHL rFVIII. Comparing OSA with CSA outcomes, Cmax resulted higher when measured by CSA ( = 0.05) and, according to TCM, Beta HL resulted longer when measured by OSA ( = 0.03). FVIII:C trough levels obtained with SHL concentrates were significantly lower than those obtained with rFVIIIFc at each post-infusion time point. In a large group of hemophilia A (HA) patients, three different PK models confirmed the improved pharmacokinetic (PK) characteristics of rFVIIIFc, compared with standard half-life rFVIII concentrates. The TCM only fits two-thirds of the PKs, highlighting their biphasic decay and a long Beta half-life. In these patients, the TCM would be preferable to properly evaluate individual PK features.
从未在大量血友病患者队列中对新型延长半衰期的FVIII浓缩物进行过房室药代动力学（PK）分析。对个体结果进行改进的PK分析可能有助于定制血友病替代治疗方案。从意大利11个血友病中心的173例重度/中度重度A型血友病患者中收集了输注标准单剂量艾美罗凝血因子α后的PK结果。所有患者均通过一期凝血试验（OSA）测量凝血因子VIII凝血活性（FVIII:C），亚组患者（n = 52）通过发色底物试验（CSA）测量。50例患者接受了与标准半衰期（SHL）重组FVIII（rFVIII）产品的比较PK评估。采用非房室分析（NCA）、一室模型（OCM）和二室模型（TCM）分析所有患者的衰减曲线，并采用单向配对方差分析比较PK结果。所有173例PK均符合NCA和OCM，但基于衰减曲线的双相特征，只有106例（61%）符合TCM。根据TCM，rFVIIIFc的β半衰期（Beta HL）和平均驻留时间（MRT）分别为20.42±7.73小时和25.64±7.61小时。对三种PK模型的结果进行方差分析，结果显示清除率、半衰期（HL）和平均驻留时间（MRT）存在显著差异（所有参数P < 0.001）。正如预期的那样，rFVIIIFc的HL和MRT比SHL rFVIII更长。比较OSA和CSA的结果，通过CSA测量时Cmax更高（P = 0.05），根据TCM，通过OSA测量时β半衰期更长（P = 0.03）。在每个输注后时间点，SHL浓缩物获得的FVIII:C谷值水平显著低于rFVIIIFc获得的水平。在一大组A型血友病（HA）患者中，三种不同的PK模型证实，与标准半衰期rFVIII浓缩物相比，rFVIIIFc具有更好的药代动力学（PK）特征。TCM仅适用于三分之二的PK，突出了它们的双相衰减和较长的β半衰期。在这些患者中，TCM更适合于正确评估个体PK特征。
