Pharmacy Department, Drug Clinical Area, University and Polytechnic Hospital La Fe, Avda. Fernando Abril Martorell 106, 46026, Valencia, Spain.
Haemostasis and Thrombosis Unit, University and Polytechnic Hospital La Fe, Avda. Fernando Abril Martorell 106, 46026, Valencia, Spain.
Thromb Res. 2019 Feb;174:151-162. doi: 10.1016/j.thromres.2018.12.027. Epub 2019 Jan 3.
Personalised pharmacokinetics (PK) using Bayesian analysis with limited sampling is assumed to help to optimise prophylaxis in haemophilia A (HA) patients.
Our prospective, observational study analysed the influence of PK parameters on clinical variables (bleeding rates, joint status, adherence, and consumption) using myPKFiT® in a cohort of twenty-one severe and moderate HA patients on prophylaxis with recombinant FVIII (Advate®) in two periods of one year, the first before PK-based tailoring and the second after PK-guided prophylaxis. Intra-individual and inter-individual coefficients of variation (CV) of half-life (t) were calculated.
A total of 73 PK estimations were performed in both periods, resulting in 17.2% inter-individual CV in mean t, and 4.9% intra-individual CV. Before PK-based tailoring a significant association between joint bleeds and t was found (P = 0.010), especially in patients with short t. This finding was reproduced (P = 0.013) after withdrawal of two patients with bleeding phenotype related to their advanced arthropathy but normal t and trough levels. Patients with joint bleeds weighed less (P = 0.039) and required higher doses (P = 0.032) than patients with zero joint bleeds. These associations were not observed in the second period after the adoption of PK-guided prophylaxis. There were no differences between the two periods, although a tendency to fewer spontaneous bleeds was suggested after PK-based tailoring.
PK-guided prophylaxis facilitates an adequate level of bleeding control in patients with HA, maintaining clinical variables and patient convenience in an integrative manner, without increasing FVIII consumption.
贝叶斯分析的个体化药代动力学（PK）与有限采样结合，被认为有助于优化血友病 A（HA）患者的预防治疗。
我们的前瞻性观察性研究使用 myPKFiT® 分析了 PK 参数对临床变量（出血率、关节状况、依从性和消耗）的影响，该研究纳入了 21 名接受预防治疗的严重和中度 HA 患者，使用重组 FVIII（Advate®）治疗，共两个为期一年的时间段，第一个时间段在基于 PK 的调整之前，第二个时间段在 PK 指导的预防治疗之后。计算了半衰期（t）的个体内和个体间变异系数（CV）。
两个时间段共进行了 73 次 PK 估算，平均 t 的个体间 CV 为 17.2%，个体内 CV 为 4.9%。在基于 PK 的调整之前，发现关节出血与 t 之间存在显著关联（P=0.010），尤其是在 t 较短的患者中。这一发现（P=0.013）在剔除两名因晚期关节病而非正常 t 和低谷水平导致出血表型的患者后得到重现。关节出血患者的体重较轻（P=0.039），需要更高的剂量（P=0.032），而非关节出血患者。这些关联在采用 PK 指导的预防治疗后的第二个时间段中并未观察到。两个时间段之间没有差异，但基于 PK 的调整后，自发性出血似乎有所减少。
PK 指导的预防治疗有助于 HA 患者获得适当的出血控制水平，以综合方式维持临床变量和患者便利性，而不会增加 FVIII 的消耗。
