Pfizer, Early Development and Clinical Pharmacology, Paris, France.
Clin Ther. 2013 Jun;35(6):782-94. doi: 10.1016/j.clinthera.2013.03.013. Epub 2013 Apr 25.
Many antidepressants are extensively metabolized in the liver, requiring dose adjustments in individuals with hepatic impairment. Clinical studies indicate that the serotonin-norepinephrine reuptake inhibitor desvenlafaxine is metabolized primarily via glucuronidation, and ∼45% is eliminated unchanged in urine.
The objectives of this study were to assess the pharmacokinetic profile, safety, and tolerability of desvenlafaxine in adults with chronic Child-Pugh class A, B, and C hepatic impairment.
Subjects (aged 18-65 years) with mild (Child-Pugh class A, n = 8), moderate (Child-Pugh class B, n = 8), and severe (Child-Pugh class C, n = 8) hepatic impairment and 12 healthy matched subjects received a single 100-mg oral dose of desvenlafaxine. Disposition of (R)-, (S)-, and (R+S)-enantiomers of desvenlafaxine were examined in plasma and urine. Geometric least squares (GLS) mean ratios and 90% CIs for AUC, AUC0-τ, Cmax, and Cl/F were calculated; comparisons were made by using a 1-factor ANOVA. Safety was evaluated according to adverse events, physical examination, vital signs, and laboratory assessments.
Healthy participants had a mean age of 51 years (range, 36-62 years) and weight of 79.1 kg (range, 52.5-105.0 kg); hepatically impaired participants had a mean age of 52 years (range, 31-65 years) and weight of 80.9 kg (range, 50.2-119.5 kg). In both groups, 67% of participants were male. No statistically significant differences (≥50%) in the disposition of desvenlafaxine were detected between hepatically impaired patients and healthy subjects based on GLS mean ratios for Cmax, AUC0-τ, AUC, or Cl/F (P > 0.05 for each comparison). Median Tmax was similar for all groups (range, 6-9 hours). A nonsignificant increase was observed for desvenlafaxine exposure in patients with moderate or severe hepatic impairment (GLS mean ratios [90% CIs] for AUC, 31% [93.2-184], 35% [96.5-190], respectively). The most common adverse events were nausea (n = 2, healthy subjects; n = 3, hepatically impaired subjects) and vomiting (n = 1, healthy subjects; n = 2, hepatically impaired subjects).
A single 100-mg dose of desvenlafaxine was well tolerated in healthy subjects and hepatically impaired patients. A mild increase in exposure was observed for moderate and severe hepatically impaired subjects (Child-Pugh class B and C).
许多抗抑郁药在肝脏中广泛代谢，因此肝功能受损的患者需要调整剂量。临床研究表明，5-羟色胺-去甲肾上腺素再摄取抑制剂去甲文拉法辛主要通过葡萄糖醛酸化代谢，约 45%以原形经尿液排泄。
本研究旨在评估去甲文拉法辛在慢性肝功能 Child-Pugh 分级 A、B 和 C 级的成年人中的药代动力学特征、安全性和耐受性。
年龄在 18-65 岁之间的轻度（Child-Pugh 分级 A，n=8）、中度（Child-Pugh 分级 B，n=8）和重度（Child-Pugh 分级 C，n=8）肝功能受损患者和 12 名健康匹配的受试者单次口服 100mg 去甲文拉法辛。在血浆和尿液中检测去甲文拉法辛的（R）-、（S）-和（R+S）-对映体的处置。使用单因素方差分析（ANOVA）计算 AUC、AUC0-τ、Cmax 和 Cl/F 的几何均数（GLS）比值和 90%置信区间（CI）；比较采用单因素方差分析。根据不良事件、体格检查、生命体征和实验室评估来评估安全性。
健康参与者的平均年龄为 51 岁（范围 36-62 岁），体重为 79.1kg（范围 52.5-105.0kg）；肝功能受损的参与者平均年龄为 52 岁（范围 31-65 岁），体重为 80.9kg（范围 50.2-119.5kg）。两组中，67%的参与者为男性。根据 Cmax、AUC0-τ、AUC 或 Cl/F 的 GLS 比值（每种比较的 P>0.05），未发现肝功能受损患者与健康受试者之间去甲文拉法辛处置有统计学意义的差异（≥50%）。所有组的中位 Tmax 相似（范围 6-9 小时）。在中度或重度肝功能受损患者中观察到去甲文拉法辛暴露的非显著增加（AUC 的 GLS 比值[90%CI]分别为 31%[93.2-184]和 35%[96.5-190]）。最常见的不良事件为恶心（健康受试者 2 例，肝功能受损受试者 3 例）和呕吐（健康受试者 1 例，肝功能受损受试者 2 例）。
在健康受试者和肝功能受损患者中，单次 100mg 剂量的去甲文拉法辛耐受性良好。在中度和重度肝功能受损患者（Child-Pugh 分级 B 和 C）中观察到暴露轻度增加。
