Evaluation of drug-drug interactions between direct-acting anti-hepatitis C virus combination regimens and the HIV-1 antiretroviral agents raltegravir, tenofovir, emtricitabine, efavirenz, and rilpivirine.
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Study Design
This was a phase 1, randomized, multiple-dose, open label, single center study to evaluate drug-drug interactions between paritaprevir/ritonavir/ombitasvir + dasabuvir (ABT-450/r/ABT-267 + ABT-333, also known as 3D regimen) and raltegravir (RAL), when administered together for 14 days in 12 healthy subjects. The 3D drugs were dosed as paritaprevir/ritonavir 150/100mg QD, ombitasvir 25mg QD, and dasabuvir 400mg BID. RAL was administered as 400mg BID, at the same time as the 3D regimen in the morning and dasabuvir in the evening. In this study, RAL was administered on days 0-3, followed by RAL plus 3D regimen on days 3-17. All doses were given under non-fasting conditions.
Blood samples for pharmacokinetic (PK) analysis were collected following dosing of RAL alone, and the combination of the two.
Study Results
Using Least Squares Mean (LSM) ratios and 90% confidence intervals (90% CI), the Cmax, AUC and Ctrough for RAL when coadministered with the 3D regimen were 2.33 (1.66-3.27), 2.34 (1.70-3.24) and 2.00 (1.17-3.42) respectively. Although the AUC of RAL was 70% to 224% higher when coadministered with the 3D regimen than alone, no dosing adjustments are required based on US prescribing information which shows that higher exposures of RAL when coadministered with omeprazole (113% to 356% higher AUC) did not prompt safety signals during phase 3 studies of RAL. Caution may be warranted in the non-healthy population due to very wide confidence intervals observed.
The Cmax and AUC of the 3D regimen components were not affected by coadministration with RAL, they were within the range of historical data.
Coadministration was generally well tolerated and no new safety findings of concern were identified.
Study Conclusions
A phase 2/3 study assessed the safety and efficacy of ABT-450/ritonavir/ombitasvir + dasabuvir + ribavirin (3D+ribavirin), in HIV-1/HCV genotype 1 co-infected subjects (n=63) on a stable atazanavir or raltegravir-inclusive regimen. Subjects recieved 3D + ribavirin for 12 or 24 weeks.
The study inlcuded HCV treatment naive (~67%), treatment experienced, and cirrhotic (19%) subjects.
An SVR12 of 93.5% was achieved in the 12 week arm and an SVR12 of 90.6% in the 24 week arm.
There were no treatment-emergent serious adverse events and no subject discontinuations due to adverse events.
Five patients had transient increases in their HIV-1 RNA (<200 copies/mL) within both arms, all patients achieved re-suppression while maintaining the same ARV regimen and without 3D + ribavirin interruption.
References
Khatri A, Dutta S, Dunbar M, Podsadecki T, Trinh R, Awni W, Menon R. Evaluation of drug-drug interactions between direct-acting anti-hepatitis c virus combination regimens and the hiv-1 antiretroviral agents raltegravir, tenofovir, emtricitabine, efavirenz, and rilpivi. Antimicrobial Agents And Chemotherapy . 2016; 5: 2965-2971.
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