Interactions with Hepatitis C Protease Inhibitors
May 1, 2013
Rilpivirine and Boceprevir
Boceprevir (BOC) is a hepatitis C virus (HCV) NS3/4A protease inhibitor used in combination with pegylated interferon + ribavirin for the treatment of HCV. As BOC is an inhibitor of hepatic cytochrome (CYP) 3A4, and many protease inhibitors and NNRTIs affect or are affected by this hepatic isoenzyme, interactions are expected. This study examined interactions between BOC and the NNRTI rilpivirine (RPV), which is metabolized by CYP3A4, in 20 HIV- and HCV-uninfected adult subjects who were given BOC 800 mg 3 times daily on days 1 to 6 followed by a 7-day washout. Subjects then were given RPV 25 mg once daily for 11 days, followed by concomitant BOC and RPV (same dosages as above) for 11 days. Pharmacokinetic and other assessments were made during each treatment period.
During coadministration of the two drugs, the geometric mean ratio for RPV AUC, Cmax, and Cmin increased 39%, 15%, and 51%, respectively, compared with the monotherapy period, whereas the BOC AUC, Cmax, and Cmin were virtually unchanged. No serious adverse events were reported.
Clinical Bottom Line
The increases in plasma RPV levels were not considered clinically significant, and based on this study, it appears that patients can be treated concurrently with RPV and BOC without dosage adjustment of either medication. However, caution should be exercised in patients at risk of QT prolongation--in early studies, RPV (at dosages of 75 mg once daily or higher) has been associated with increased risk of QT prolongation.
- Rhee E, Feng HP, Xuan F, et al. Absence of a significant pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and HIV-1 NNRTI rilpivirine. In: Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta. Abstract 537.
Ribavirin and Telaprevir
High rates of anemia have been observed in patients receiving the hepatitis C virus (HCV) protease inhibitors telaprevir (TVR) or boceprevir in combination with pegylated interferon + ribavirin (PR). The present investigation (part of an ongoing randomized study of HCV treatment) evaluated a potential interaction between TVR and ribavirin by measuring ribavirin concentrations in the plasma and within red blood cells and peripheral blood mononuclear cells (PBMCs) in hepatitis C-monoinfected patients receiving TVR + PR compared with PR alone.
Twenty-one HCV-monoinfected subjects, 5 on TVR + PR and 16 on PR alone, underwent intensive pharmacokinetic sampling for ribavirin levels at steady state. Dosage-adjusted plasma and intracellular ribavirin levels were higher in persons receiving TVR + PR compared with those receiving PR alone: The ribavirin AUC0-12 was 1.54-fold higher, and ribavirin monophosphate, ribavirin diphosphate, and ribavirin triphosphate concentrations in red blood cells were 3.3 times higher, 2.3 times higher, and 2.4 times higher, respectively. The differences in levels in phosphorylated ribavirin levels in PBMCs similarly were 2-3 times higher in TVR + PR subjects compared with PR-only subjects. All comparisons were statistically significant. Hemoglobin decreases were -5.5 g/dL in those on TVR + PR compared with -4.3 g/dL in those on PR alone; this difference was not statistically significant.
Clinical Bottom Line
This study provides evidence that TVR increases plasma and intracellular ribavirin concentrations. This may be responsible for the increased incidence rate of anemia observed in patients treated with TVR + PR, but the findings will have to be confirmed in larger numbers of subjects. Meanwhile, the mechanism for the apparent interaction is not known.
- Hammond K, Jimmerson L, MacBrayne C, et al. Increased Plasma and intracellular ribavirin concentrations associated with telaprevir use. In: Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta. Abstract #34.
Darunavir/Ritonavir, Efavirenz, and Tenofovir with Faldaprevir
Faldaprevir (FDV) is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor currently being studied in Phase III clinical trials. Because FDV is both a substrate and inhibitor of CYP450 3A4 and an inhibitor of CYP 2C9, interactions with many antiretrovirals are expected.
In a presentation at CROI, data on FDV interactions was taken from 3 pharmacokinetic studies, each with a different protocol, that separately evaluated FDV interactions with efavirenz (EFV), with darunavir + ritonavir (DRV/r), and with tenofovir (TDF) in healthy subjects.
When EFV was given with FDV (240 mg BID) as well as a single oral dose of midazolam (7.5 mg), the FDV AUC decreased 35% and Cmin decreased 46%; no information was given on changes in EFV levels.
When DRV/r (800 mg/100 mg once daily) was coadministered with FDV (240 mg QD), the DRV AUC increased 15% and the Cmin decreased 12%. FDV levels evidently were not measured during a monotherapy phase, but FDV levels measured during coadministration with DRV/r were compared with those from a different study of FDV monotherapy. By this comparison, the FDV AUC was 129% higher and the Cmax was 64% higher in subjects given FDV with DRV/r.
When TDF was given with FDV, the TDF AUC increased by 22%. FDV AUC and Cmin when coadministered with TDF were lower by 22% and 25%, respectively, by comparison with the different cohort on FDV alone.
No serious adverse effects were reported, though gastrointestinal symptoms were more common with FDV 240 mg BID dosing.
Clinical Bottom Line
The different protocols used in the 3 interactions studies presented above, and the cross-study comparisons, make it difficult to assess these data, and these studies will need to be conducted in a cleaner and clearer way. Nevertheless, the reported differences in FDV levels when coadministered with EFV or DRV/r, if true, are likely to be clinically significant, although the effects of FDV on the concentrations of these ARVs are not. Studies involving dosage modification of FDV in the setting of these coadministered ARVs are under way.
- Sabo J, Kort J, Haschke M, et al. Pharmacokinetic interactions of darunavir/ritonavir, efavirenz, and tenofovir with the hepatitis C virus protease inhibitor faldaprevir in healthy volunteers. In: Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta. Abstract 35.
Susa Coffey is medical editor of the NCRC. She is a Professor of Medicine at UCSF in the Division of HIV, Infectious Diseases and Global Medicine and a longtime clinician and educator in the HIV at San Francisco General Hospital clinic (“Ward 86”). She also is medical editor of HIV InSite.