背景:Rezafungin是第二代,每周一次的棘白菌素抗真菌药物被批准用于治疗侵袭性念珠菌病,包括念珠菌病。在瑞扎芬净与卡泊芬净的II/III期研究中,由于该人群中缺乏卡泊芬净数据,严重肝功能损害患者被排除.这个开放标签,单剂量,I期研究评估了瑞扎芬净在中度或重度肝功能损害患者中的药代动力学(主要目标)和安全性,肝功能正常的健康受试者。
方法:8名中度(Child-PughB)或重度(Child-PughC)肝功能损害的受试者与健康受试者的年龄1:1匹配,性别,和体重指数。每个受试者接受一次400毫克,静脉注射,1小时输注rezafungin。在给药后336小时的不同时间点进行血浆药代动力学采样。通过非房室分析得出药代动力学参数。在整个过程中对安全性进行了评估。
结果:所有32名受试者均接受研究治疗,并纳入所有分析。尽管总血浆浓度分布重叠,基于几何最小二乘(LS)平均比率,在中度受试者中,从时间零(开始输注之前)到无穷大(AUC0-∞)的血浆浓度-时间曲线下面积降低了32%(LS平均比率,67.55;90%置信区间[CI]:53.91,84.65)和严重(LS均值比,67.84;90%CI:57.49,80.05)肝功能损害与匹配的健康受试者。中度肝功能损害组的最大血浆浓度(Cmax)降低了12%,重度肝功能损害组降低了28%。线性回归显示肝功能损害程度(基于Child-Pugh评分)在AUC0-∞或Cmax上没有显着趋势(p>0.05)。7名受试者报告了因治疗引起的不良事件(21.9%;每个肝功能损害组中有3名受试者,和一个健康的受试者),没有一个是严重的,严肃,或导致退出。
结论:Rezafungin耐受性良好,可用于中度或重度肝功能损害患者,无需调整剂量。在肝功能损害受试者中暴露的适度减少在临床上没有意义,并且不太可能影响疗效。
BACKGROUND: Rezafungin is a second-generation, once-weekly echinocandin antifungal approved for the treatment of invasive candidiasis, including candidemia. In phase II/III studies of rezafungin versus caspofungin, patients with severe hepatic impairment were excluded due to lack of caspofungin data in this population. This open-label, single-dose, phase I study evaluated the pharmacokinetics (primary objective) and safety of rezafungin in subjects with moderate or severe hepatic impairment versus matched, healthy subjects with normal hepatic function.
METHODS: Eight subjects each with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment were matched 1:1 with healthy subjects for age, sex, and body mass index. Each subject received a single 400-mg, intravenous, 1-h infusion of rezafungin. Plasma pharmacokinetic sampling was performed at various time points through 336 h postdose. Pharmacokinetic parameters were derived by non-compartmental analysis. Safety was assessed throughout.
RESULTS: All 32 subjects received study treatment and were included in all analyses. Despite overlapping distributions of total plasma concentrations, based on geometric least-squares (LS) mean ratios, the area under the plasma concentration-time curve from time zero (prior to the start of infusion) to infinity (AUC0-∞) was 32% lower in subjects with moderate (LS mean ratio, 67.55; 90% confidence interval [CI]: 53.91, 84.65) and severe (LS mean ratio, 67.84; 90% CI: 57.49, 80.05) hepatic impairment versus matched healthy subjects. The maximum plasma concentration (Cmax) was 12% lower in moderate hepatic impairment and 28% lower in severe hepatic impairment groups. Linear regression showed no significant trend in the degree of hepatic impairment (based on Child-Pugh score) on AUC0-∞ or Cmax (p > 0.05). Treatment-emergent adverse events were reported in seven subjects (21.9%; three subjects in each of the hepatic impairment groups, and one healthy subject), none of which were severe, serious, or resulted in withdrawal.
CONCLUSIONS: Rezafungin is well tolerated and can be administered to patients with moderate or severe hepatic impairment without the need for dose adjustment. The modest reduction in exposures in subjects with hepatic impairment is not clinically meaningful and is unlikely to impact efficacy.