Björkman S, Shapiro A D, Berntorp E
Hospital Pharmacy, Malmö University Hospital, Malmö, Sweden.
Haemophilia. 2001 Mar;7(2):133-9. doi: 10.1046/j.1365-2516.2001.00465.x.
The aims of this study were to investigate possible age-related changes in the disposition of factor IX procoagulant activity (FIX:C) after administration of recombinant factor IX (rFIX) and to translate the pharmacokinetic findings into suggestions for dosing of rFIX during prophylactic treatment of haemophilia B. Pharmacokinetic data were available from a previous study on 56 patients, aged 4-56 years (one of whom was excluded from analysis). FIX:C curves during prophylactic dosing were computer-simulated from the single-dose data. Clearance and volume of distribution at steady state of FIX:C increased linearly with body weight of the patients, consequently increasing during childhood and adolescence but remaining fairly constant during adulthood. The terminal half-life of FIX:C showed no correlation with age, while in vivo recovery (in U dL(-1) per U kg(-1) given) tended to increase. Computer-predicted trough levels of exogenous FIX:C during repeated doses of rFIX (50 U kg(-1)) and, conversely, doses (in U kg(-1)) needed to maintain a 1-U dL(-1) trough level showed little or no dependence on age. There was considerable interindividual variation in disposition and required doses of rFIX, emphasizing the need for individual dose titration. Dosing of rFIX according to lean body mass instead of body weight did not reduce this variability. During prophylaxis a 1-U dL(-1) trough level can normally be maintained by dosing every 2-3 days, the former schedule resulting in, on average, a 45% lower consumption of rFIX.
本研究的目的是调查重组凝血因子IX（rFIX）给药后，凝血因子IX促凝活性（FIX:C）的处置可能存在的年龄相关变化，并将药代动力学研究结果转化为对B型血友病预防性治疗期间rFIX给药剂量的建议。药代动力学数据来自之前一项针对56例年龄在4至56岁患者的研究（其中1例被排除在分析之外）。预防性给药期间的FIX:C曲线是根据单剂量数据通过计算机模拟得到的。FIX:C的清除率和稳态分布容积随患者体重呈线性增加，因此在儿童期和青春期增加，但在成年期保持相当稳定。FIX:C的终末半衰期与年龄无关，而体内回收率（每给予1 U kg⁻¹的U dL⁻¹）有增加趋势。计算机预测的rFIX重复给药（50 U kg⁻¹）期间外源性FIX:C的谷浓度，以及相反地，维持1 U dL⁻¹谷浓度所需的剂量（U kg⁻¹）对年龄的依赖性很小或没有依赖性。rFIX的处置和所需剂量存在相当大的个体间差异，强调了个体剂量滴定的必要性。根据瘦体重而非体重给药rFIX并没有减少这种变异性。在预防性治疗期间，通常每2至3天给药一次可维持1 U dL⁻¹的谷浓度，前一种给药方案平均可使rFIX的消耗量降低45%。
