Patel Krishna R, Blair Christiana J, Tislow James D
1 Gilead Sciences Inc., Miami, FL, USA.
2 Gilead Sciences Inc., Foster City, CA, USA.
Pulm Circ. 2018 Oct-Dec;8(4):2045894018797273. doi: 10.1177/2045894018797273. Epub 2018 Aug 20.
Treatment with endothelin receptor antagonists (ERA) can result in adverse hepatic effects in patients with pulmonary arterial hypertension (PAH). We evaluated the hepatic safety of ambrisentan (ABS), an ERA, used as monotherapy, or with tadalafil (TAD), a phosphodiesterase-5 (PDE5) inhibitor as initial combination therapy (ABS + TAD) in the AMBITION trial. This was a retrospective analysis set in academic and private outpatient clinics and research centers. This analysis included 596 patients with PAH who were randomized to ABS or TAD as monotherapy or ABS + TAD as initial combination therapy and received at least one dose of study drug, and who had baseline and follow-up hepatic function data. Treatment options following a clinical failure event included blinded combination therapy (BCT). The proportion of patients with elevations in alanine or aspartate aminotransferases (ALT/AST) > 3 × upper limit of normal (ULN), and those with total bilirubin (TBili) > 2× ULN and ALT or AST > 3 × ULN (referred to as potential Hy's law), were determined before BCT as well as including time on BCT. Elevations in ALT/AST > 3 × ULN during the study were in the range of 3.4-3.7%, with an annualized incidence of 2.1-2.93%. The majority of patients with elevations in ALT/AST had elevations > 3 to ≤ 5 × ULN. Three patients (0.5%) had ALT/AST > 3 × ULN plus TBili > 2 × ULN. All three patients had probable alternative causes (cardiogenic shock, liver metastases, lymphoma) for the elevations. Our analysis of the AMBITION trial demonstrated that ABS and ABS + TAD were not associated with drug-induced liver injury.
内皮素受体拮抗剂（ERA）治疗可导致肺动脉高压（PAH）患者出现肝脏不良反应。我们在AMBITION试验中评估了作为单一疗法使用的ERA安立生坦（ABS），或与磷酸二酯酶-5（PDE5）抑制剂他达拉非（TAD）联合作为初始联合疗法（ABS + TAD）的肝脏安全性。这是一项在学术和私立门诊诊所及研究中心进行的回顾性分析。该分析纳入了596例PAH患者，这些患者被随机分配接受ABS或TAD单一疗法，或ABS + TAD作为初始联合疗法，并接受了至少一剂研究药物，且有基线和随访肝功能数据。临床失败事件后的治疗选择包括盲法联合疗法（BCT）。在BCT之前以及纳入BCT治疗时间后，确定丙氨酸或天冬氨酸转氨酶（ALT/AST）升高>3×正常上限（ULN）的患者比例，以及总胆红素（TBili）>2×ULN且ALT或AST>3×ULN（称为潜在的Hy法则）的患者比例。研究期间ALT/AST升高>3×ULN的比例在3.4% - 3.7%之间，年化发病率为2.1% - 2.93%。大多数ALT/AST升高的患者升高幅度>3至≤5×ULN。3例患者（0.5%）ALT/AST>3×ULN且TBili>2×ULN。所有3例患者的升高可能都有其他原因（心源性休克、肝转移、淋巴瘤）。我们对AMBITION试验的分析表明，ABS和ABS + TAD与药物性肝损伤无关。
