Takahashi H, Ishikawa S, Nomoto S, Nishigaki Y, Ando F, Kashima T, Kimura S, Kanamori M, Echizen H
Department of Pharmacotherapy, Meiji Pharmaceutical University, Tokyo, Japan.
Clin Pharmacol Ther. 2000 Nov;68(5):541-55. doi: 10.1067/mcp.2000.110977.
To clarify developmental changes in the pharmacokinetics and dynamics of warfarin enantiomers to establish rational pediatric dosage.
Plasma concentrations of unbound warfarin enantiomers, vitamin K1 and vitamin K-dependent proteins (that is, prothrombin fragments 1+2, protein C, and the protein-induced by vitamin K absence) and international normalized ratio were measured in 38 prepubertal (1 to 11 years), 15 pubertal (12 to 18 years), and 81 adult (37 to 76 years) patients given long-term warfarin therapy. Unbound oral clearance values for warfarin enantiomers and its body weight-, body surface area-, and liver weight-normalized values, as well as the pharmacodynamic parameters, were compared among the groups.
The prepubertal, pubertal, and adult patients exhibited comparable mean plasma concentrations of unbound warfarin enantiomers for pharmacologically more active (S)-warfarin. Although the unbound oral clearance of (S)-warfarin for the prepubertal patients was significantly (P < .01) less than that for the adult group (346 versus 637 mL/min), the body weight-normalized unbound oral clearance for the prepubertal patients was significantly (P < .01) greater than that for the adults and showed a negative correlation (P < .05) with age. In contrast, no differences were observed in the liver weight-normalized unbound oral clearance for (S)-warfarin between the prepubertal and adult groups. The prepubertal patients showed significantly (P < .01 or .05) lower plasma concentrations of protein C and prothrombin fragments 1+2 and greater international normalized ratio and international normalized ratio/dose than the adults. In contrast, the pubertal patients showed largely similar pharmacokinetic and pharmacodynamic properties to adults.
Liver weight may be a better parameter than body weight for estimating the warfarin doses for prepubertal patients on the basis of the corresponding adult values. Augmented responses to warfarin in children should also be taken into account for estimating warfarin doses for children.
阐明华法林对映体的药代动力学和药效学的发育变化，以确定合理的儿科剂量。
在38例青春期前（1至11岁）、15例青春期（12至18岁）和81例成人（37至76岁）接受长期华法林治疗的患者中，测量了游离华法林对映体、维生素K1和维生素K依赖性蛋白（即凝血酶原片段1+2、蛋白C和维生素K缺乏诱导蛋白）的血浆浓度以及国际标准化比值。比较了各组间华法林对映体的游离口服清除率值及其体重、体表面积和肝脏重量标准化值，以及药效学参数。
青春期前、青春期和成人患者中，药理活性更强的（S）-华法林的游离血浆平均浓度相当。虽然青春期前患者的（S）-华法林游离口服清除率显著低于成人组（P < 0.01）（346对637 mL/min），但青春期前患者的体重标准化游离口服清除率显著高于成人（P < 0.01），且与年龄呈负相关（P < 0.05）。相比之下，青春期前和成人组之间（S）-华法林的肝脏重量标准化游离口服清除率没有差异。青春期前患者的蛋白C和凝血酶原片段1+2的血浆浓度显著低于成人（P < 0.01或0.05），国际标准化比值和国际标准化比值/剂量则高于成人。相比之下，青春期患者的药代动力学和药效学特性与成人基本相似。
在根据相应的成人值估算青春期前患者的华法林剂量时，肝脏重量可能比体重是更好的参数。在估算儿童华法林剂量时，还应考虑儿童对华法林反应增强的情况。
Zotero 插件