Effects of chronic kidney disease stage 4, end-stage renal disease, or dialysis on the plasma concentrations of ombitasvir, paritaprevir, ritonavir, and dasabuvir in patients with chronic HCV infection: pharmacokinetic analysis of the phase 3 RUBY-I and RUBY-II trials
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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 (Ctrough) 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 Ctrough 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)
KeywordsHepatitis C virus End-stage renal disease Chronic kidney disease Renal impairment Ombitasvir/paritaprevir/ritonavir Dasabuvir
The authors thank the clinical sites, investigators, and AbbVie Drug Analysis. The authors thank Sonja Kemmis Causemaker, an employee of AbbVie, for her medical writing support.
Diana L. Shuster, Rajeev M. Menon, Bifeng Ding, Amit Khatri, Hong Li, Eric Cohen, Melissa Jewett, Daniel E. Cohen, and Jiuhong Zha contributed to the study design and analysis and interpretation of the data as well as the drafting and revising of the manuscript.
AbbVie provided financial support for the studies and participated in the design, study conduct, analysis, and interpretation of data as well as the writing, review, and approval of the manuscript.
Compliance with ethical standards
Conflict of interest
DLS, RMM, BD, AK, HL, EC, DEC, and JZ are current or former employees of AbbVie and may hold AbbVie stock and/or stock options. MJ is a contractor of AbbVie, employed by InVentiv Health.
The studies were conducted in accordance with International Council for Harmonization Good Clinical Practice guidelines and ethical principles that have their origin in the Declaration of Helsinki. The study protocols were approved by the independent ethics committees/institutional review boards.
Informed consent was obtained from all individual participants included in the studies.
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