Shuster Diana L, Menon Rajeev M, Ding Bifeng, Khatri Amit, Li Hong, Cohen Eric, Jewett Melissa, Cohen Daniel E, Zha Jiuhong
Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
Eur J Clin Pharmacol. 2019 Feb;75(2):207-216. doi: 10.1007/s00228-018-2566-6. Epub 2018 Oct 5.
To characterize the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, dasabuvir, and ribavirin in hepatitis C virus (HCV)-infected patients with chronic kidney disease stage 4 (CKD4) or end-stage renal disease (ESRD), including those on dialysis, in the open-label phase 3 RUBY-I and RUBY-II studies.
Patients (n = 18 CKD4, n = 68 ESRD) received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± dasabuvir 250 mg twice daily ± ribavirin 200 mg once daily for 12 or 24 weeks. Intensive pharmacokinetic samples were collected from ten patients; sparse samples were collected from all patients. Arterial and venous samples were collected from three patients during hemodialysis. Area under the plasma concentration-time curve (AUC) was estimated using noncompartmental analyses for intensive data, and steady-state trough concentrations (C) were obtained from the sparse data. Pharmacokinetic results from RUBY-I and RUBY-II were compared empirically to historical data.
The AUC values of ombitasvir, paritaprevir, ritonavir, and dasabuvir were comparable between CKD4 and ESRD patients and were within the range of values observed in historical studies; dialysis had no effect on drug exposures. Ribavirin was extracted during hemodialysis but had similar exposures on dialysis and non-dialysis days. Individual steady-state C values for each drug overlapped between CKD4 and ESRD patients, and values in both groups were similar to historical values.
Plasma concentrations of ombitasvir, paritaprevir, ritonavir, and dasabuvir were not altered by renal impairment or dialysis, suggesting these agents can be administered to HCV-infected CKD4 or ESRD patients, including those on dialysis, without dose adjustment.
Clinicaltrials.gov identifiers: NCT02207088 (RUBY-I) and NCT02487199 (RUBY-II).
在开放标签的3期RUBY - I和RUBY - II研究中，对慢性肾脏病4期（CKD4）或终末期肾病（ESRD），包括接受透析治疗的丙型肝炎病毒（HCV）感染患者中，奥比他韦、帕利哌韦、利托那韦、达沙布韦和利巴韦林的药代动力学进行特征描述。
患者（18例CKD4患者，68例ESRD患者）接受奥比他韦/帕利哌韦/利托那韦25/150/100毫克每日一次，±达沙布韦250毫克每日两次，±利巴韦林200毫克每日一次，持续12或24周。从10例患者中采集密集药代动力学样本；从所有患者中采集稀疏样本。在血液透析期间从3例患者中采集动脉和静脉样本。使用非房室分析法对密集数据估算血浆浓度-时间曲线下面积（AUC），并从稀疏数据中获得稳态谷浓度（C）。将RUBY - I和RUBY - II的药代动力学结果与历史数据进行经验性比较。
CKD4和ESRD患者中，奥比他韦、帕利哌韦、利托那韦和达沙布韦的AUC值具有可比性，且在历史研究观察到的值范围内；透析对药物暴露无影响。利巴韦林在血液透析期间被清除，但透析日和非透析日的暴露情况相似。CKD4和ESRD患者中每种药物的个体稳态C值有重叠，且两组的值与历史值相似。
肾功能损害或透析未改变奥比他韦、帕利哌韦、利托那韦和达沙布韦的血浆浓度，提示这些药物可用于HCV感染的CKD4或ESRD患者，包括接受透析治疗的患者，无需调整剂量。
Clinicaltrials.gov标识符：NCT02207088（RUBY - I）和NCT02487199（RUBY - II）。
