Armetheon, Menlo Park, California United States.
Stanford University, Palo Alto, California, United States.
Thromb Haemost. 2017 Nov;117(11):2026-2033. doi: 10.1160/TH16-10-0815. Epub 2017 Nov 30.
Chronic kidney disease (CKD) complicates warfarin anticoagulation partially through its effect on CYP2C9 activity. Tecarfarin, a novel vitamin K antagonist, is not metabolized by CYP2C9. To evaluate the effect of CKD on their metabolism, we measured PK parameters of warfarin and tecarfarin in subjects with and without CKD. CKD subjects with estimated glomerular filtration rate < 30 mL/min not on dialysis ( = 13) were matched to healthy volunteers (HVs) ( = 10). Each subject was randomized to either warfarin 10 mg or tecarfarin 30 mg and was later crossed over to the other drug. PK parameters were measured following each drug. Mean plasma concentrations of (S)-warfarin and (R,S)-warfarin were higher (44 and 27%, respectively) in the subjects with CKD than in the healthy subjects. Both of these values fell outside of the 90% confidence interval of equivalence. For tecarfarin, the difference was less than 15% higher. Elimination half-life () increased by 20% for (S)-warfarin and by 8% for (R,S)-warfarin and decreased by 8% for tecarfarin. The mean plasma concentration for tecarfarin's inactive metabolite ATI-5900 increased by approximately eightfold. CKD increased the effect of CYP2C9 genetic variation on (S)-warfarin and (R,S)-warfarin metabolism. Tecarfarin exposure was similar between the HVs and the CKD subjects regardless of CYP2C9 genotype. There were neither serious adverse events (SAEs) nor treatment-emergent adverse events (TEAEs) for any subject in the study. CKD inhibits metabolism of (S)-warfarin and (R,S)-warfarin, but not tecarfarin. The safety of repeated dosing of tecarfarin in CKD patients remains unknown. However, if the PK findings of this single-dose study are present with repeated dosing, tecarfarin may lead to dosing that is more predictable than warfarin in CKD patients who require anticoagulation therapy.
慢性肾脏病（CKD）部分通过其对 CYP2C9 活性的影响使华法林抗凝复杂化。替卡法林是一种新型的维生素 K 拮抗剂，不由 CYP2C9 代谢。为了评估 CKD 对其代谢的影响，我们在 CKD 患者和非 CKD 患者中测量了华法林和替卡法林的 PK 参数。未接受透析的估计肾小球滤过率 < 30 mL/min 的 CKD 患者（ = 13）与健康志愿者（HV）相匹配（ = 10）。每位受试者随机接受华法林 10mg 或替卡法林 30mg，随后交叉至另一药物。每次给药后均测量 PK 参数。与健康受试者相比，（S）-华法林和（R，S）-华法林的（S）-华法林和（R，S）-华法林的平均血浆浓度均升高（分别为 44%和 27%）。这两个值都超出了等效性的 90%置信区间。替卡法林的差异小于 15%。（S）-华法林的消除半衰期（）增加了 20%，（R，S）-华法林的半衰期增加了 8%，替卡法林的半衰期减少了 8%。替卡法林无活性代谢物 ATI-5900 的平均血浆浓度增加了约 8 倍。CKD 增加了 CYP2C9 遗传变异对华法林和（R，S）-华法林代谢的影响。无论 CYP2C9 基因型如何，替卡法林在 HV 和 CKD 患者中的暴露量相似。研究中没有发生任何受试者的严重不良事件（SAE）或治疗中出现的不良事件（TEAE）。CKD 抑制（S）-华法林和（R，S）-华法林的代谢，但不抑制替卡法林的代谢。在 CKD 患者中重复给予替卡法林的安全性仍未知。然而，如果单次给药研究的 PK 发现存在于重复给药中，替卡法林可能会导致比华法林更可预测的剂量，在需要抗凝治疗的 CKD 患者中。
