Baur Brian P, Meaney Calvin J
University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York.
Pharmacotherapy. 2014 Jun;34(6):605-16. doi: 10.1002/phar.1421. Epub 2014 Apr 7.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by bilateral renal cysts, kidney pain, hypertension, and progressive loss of renal function. It is a leading cause of end-stage renal disease and the most common inherited kidney disease in the United States. Despite its prevalence, disease-modifying treatment options do not currently exist. Tolvaptan is an orally active, selective arginine vasopressin V2 receptor antagonist already in use for hyponatremia. Tolvaptan exhibits dose-proportional pharmacokinetics with a half-life of ~12 hours. Metabolism occurs through the cytochrome P450 3A4 isoenzyme, and tolvaptan is a substrate for P-glycoprotein, resulting in numerous drug interactions. Recent research has highlighted the beneficial effect of tolvaptan on delaying the progression of ADPKD, which is the focus of this review. Pharmacologic, preclinical, and phase II and III clinical trial studies have demonstrated that tolvaptan is an effective treatment option that targets underlying pathogenic mechanisms of ADPKD. Tolvaptan delays the increase in total kidney volume (surrogate marker for disease progression), slows the decline in renal function, and reduces kidney pain. However, tolvaptan has significant adverse effects including aquaretic effects (polyuria, nocturia, polydipsia) and elevation of aminotransferase enzyme concentrations with the potential for acute liver failure. Appropriate patient selection is critical to optimize long-term benefits while minimizing adverse effects and hepatotoxic risk factors. Overall, tolvaptan is the first pharmacotherapeutic intervention to demonstrate significant benefit in the treatment of ADPKD, but practitioners and regulatory agencies must carefully weigh the risks versus benefits. Additional research should focus on incidence and risk factors of liver injury, cost-effectiveness, clinical management of drug-drug interactions, and long-term disease outcomes.
常染色体显性多囊肾病（ADPKD）的特征为双侧肾囊肿、肾区疼痛、高血压以及肾功能的进行性丧失。它是终末期肾病的主要病因，也是美国最常见的遗传性肾病。尽管其患病率较高，但目前尚无改善病情的治疗方法。托伐普坦是一种口服活性的选择性精氨酸加压素V2受体拮抗剂，已用于治疗低钠血症。托伐普坦呈现剂量比例性药代动力学，半衰期约为12小时。其代谢通过细胞色素P450 3A4同工酶进行，且托伐普坦是P-糖蛋白的底物，这导致了众多药物相互作用。近期研究突出了托伐普坦在延缓ADPKD进展方面的有益作用，这也是本综述的重点。药理学、临床前以及II期和III期临床试验研究表明，托伐普坦是一种针对ADPKD潜在致病机制的有效治疗选择。托伐普坦可延缓总肾体积的增加（疾病进展的替代标志物），减缓肾功能下降，并减轻肾区疼痛。然而，托伐普坦具有显著的不良反应，包括排水利尿作用（多尿、夜尿、烦渴）以及转氨酶浓度升高，有引发急性肝衰竭的可能。恰当的患者选择对于在将不良反应和肝毒性风险因素降至最低的同时优化长期益处至关重要。总体而言，托伐普坦是首个在治疗ADPKD中显示出显著益处的药物治疗干预措施，但从业者和监管机构必须仔细权衡风险与益处。进一步的研究应聚焦于肝损伤的发生率和风险因素、成本效益、药物相互作用的临床管理以及长期疾病转归。
