Herbert Robert D, Broderick Carolyn R, Barnes Chris, Billot Laurent, Zhou Albert, Latimer Jane
Neuroscience Research Australia (NeuRA), Randwick, NSW, Australia.
University of New South Wales, Kensington, NSW, Australia.
PLoS One. 2018 Feb 15;13(2):e0192783. doi: 10.1371/journal.pone.0192783. eCollection 2018.
BACKGROUND & AIMS: Prophylactic injections of factor VIII reduce the incidence of bleeds and slow the development of joint damage in people with hemophilia. The aim of this study was to identify optimal person-specific prophylaxis regimens for children with hemophilia A.
Analytic and numerical methods were used to identify prophylaxis regimens which maximize the time for which plasma factor VIII concentrations exceed a threshold, maximize the lowest plasma factor VIII concentrations, and minimize risk of bleeds.
It was demonstrated analytically that, for any injection schedule, the regimen that maximizes the lowest factor VIII concentration involves sharing doses between injections so that all of the trough concentrations in a prophylaxis cycle are equal. Numerical methods were used to identify optimal prophylaxis schedules and explore the trade-offs between efficacy and acceptability of different prophylaxis regimens. The prophylaxis regimen which minimizes risk of bleeds depends on the person's pattern of physical activity and may differ greatly from prophylaxis regimens that optimize pharmacokinetic parameters. Prophylaxis regimens which minimize risk of bleeds also differ from prophylaxis regimens that are typically prescribed. Predictions about which regimen is optimal are sensitive to estimates of the effects on risk of bleeds of factor VIII concentration and physical activity.
The methods described here can be used to identify optimal, person-specific prophylaxis regimens for children with hemophilia A.
预防性注射凝血因子 VIII 可降低血友病患者出血的发生率，并减缓关节损伤的发展。本研究的目的是确定针对甲型血友病儿童的最佳个体化预防方案。
采用分析和数值方法来确定预防方案，这些方案要使血浆凝血因子 VIII 浓度超过阈值的时间最大化，使最低血浆凝血因子 VIII 浓度最大化，并使出血风险最小化。
分析表明，对于任何注射方案，使最低凝血因子 VIII 浓度最大化的方案是在各次注射之间分配剂量，以便预防周期内所有谷浓度相等。采用数值方法确定最佳预防方案，并探讨不同预防方案在疗效和可接受性之间的权衡。使出血风险最小化的预防方案取决于个体的身体活动模式，可能与优化药代动力学参数的预防方案有很大差异。使出血风险最小化的预防方案也与通常规定的预防方案不同。关于哪种方案最佳的预测对凝血因子 VIII 浓度和身体活动对出血风险影响的估计很敏感。
本文所述方法可用于确定针对甲型血友病儿童的最佳个体化预防方案。
