PDF(Pubmed)
Abstract：
Background: Tolvaptan, a selective vasopressin V2-receptor antagonist, can elicit a diuretic effect without significant electrolyte loss. The aims were to evaluate multiple-dose pharmacokinetics, pharmacodynamics and safety of daily administration of 15 mg tolvaptan in Chinese adult patients with confirmed Child-Pugh Class B cirrhosis accompanied by ascites. Methods: This was an open-label, single-center, single- and multiple-dose study. All patients received a daily 15 mg dose of tolvaptan for 7 consecutive days. The plasma concentrations of tolvaptan and its two metabolites (DM-4103, DM-4107) were measured using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). In addition, various pharmacokinetics parameters were calculated. The pharmacodynamic outcomes evaluated changes in serum sodium and potassium concentrations, daily urine volume, daily water consumption, fluid balance and body weight. Safety profiles, including the incidence of treatment-emergent adverse events (TEAEs), were carefully recorded. Results: Eleven patients with Child-Pugh B cirrhosis were eventually enrolled in the study. Plasma concentrations of tolvaptan and DM-4107 reached steady-states after 7 days of consecutive oral administration. No accumulation of tolvaptan or DM-4107 was found, but DM-4103 accumulated 18.2-fold after multiple-dosing. The daily urine volume and daily water consumption were statistically significantly increased after administration of tolvaptan from Day 1 to Day 7 (all p < 0.05), accompanied by an increased serum sodium concentration. Of 11 patients, 9 (81.8%) reported 20 TEAEs, with the majority being mild to moderate in severity. The most commonly occurring TEAEs were thirst (45.5%), pollakiuria (36.4%) and dry mouth (27.3%). Conclusion: Tolvaptan at a daily dose of 15 mg had a diuretic effect but did not increase serum sodium excretion or lead to tolvaptan accumulation. It is therefore can be safely used for short-term treatment of Chinese adult patients with confirmed Child-Pugh B cirrhosis. Clinical Trial Registration: https://clinicaltrials.gov/search?term=NCT01359462, identifier NCT01359462.
摘要：
背景：托伐普坦，选择性加压素V2受体拮抗剂，可以引起利尿作用而没有明显的电解质损失。目的是评估多剂量药代动力学，在确诊为Child-PughB级肝硬化伴腹水的中国成年患者中，每日服用15mg托伐普坦的药效学和安全性。方法：这是一个开放标签，单中心,单剂量和多剂量研究。所有患者连续7天接受每日15mg剂量的托伐普坦。使用高效液相色谱-串联质谱（HPLC-MS/MS）测量托伐普坦及其两种代谢物（DM-4103，DM-4107）的血浆浓度。此外,计算了各种药代动力学参数。药效学结果评估了血清钠和钾浓度的变化，每日尿量,每日用水量,液体平衡和体重。安全概况,包括因治疗引起的不良事件（TEAE）的发生率，被仔细记录。结果：11例Child-PughB肝硬化患者最终纳入研究。托伐普坦和DM-4107的血浆浓度在连续口服给药7天后达到稳态。没有发现托伐普坦或DM-4107的积累，但DM-4103在多次给药后累积了18.2倍。从第1天到第7天服用托伐普坦后，每日尿量和每日用水量在统计学上显著增加（均p<0.05），伴随着血清钠浓度的增加。在11名患者中，9人（81.8%）报告了20个TEAE，大多数是轻度至中度的严重程度。最常见的TEAE是口渴（45.5％），尿频(36.4%)和口干(27.3%)。结论：托伐普坦日剂量为15mg具有利尿作用，但不会增加血清钠排泄或导致托伐普坦积累。因此，它可以安全地用于中国成年患者确诊的Child-PughB肝硬化的短期治疗。临床试验注册：https://clinicaltrials.gov/search?term=NCT01359462，标识符NCT01359462。
