Special Dosing considerations should be followed, but dose adjustments are not warranted.
). TURQUOISE-I study: use of ombitasvir/paritaprevir/ritonavir+ dasabuvir+ ribavirin in patients with HCV/HIV-1 co-infection on stable darunavir-containing antiretroviral therapy [abstract LBPS7/1].
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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 darunavir (DRV), when administered together for 14 days in healthy subjects. The 3D drugs were dosed as paritaprevir/ritonavir 150/100mg QD, ombitasvir 25mg QD, and dasabuvir 400mg BID. (Dasabuvir 250mg optimized tablets, given twice daily were used in the group receiving once-daily evening administration of DRV). Darunavir was administered as 800mg QD in the morning or in the evening or 600mg BID. Ritonavir was only given with the evening doses of darunavir since the 3D regimen provided ritonavir for the morning doses.
Blood samples for pharmacokinetic (PK) analysis were collected following dosing of the 3D regimen alone, boosted darunavir 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 DRV when coadministered with the 3D regimen were 0.92 (0.87-0.98), 0.76 (0.71-0.82) and 0.52 (0.47-0.58), respectively, when dosed in the morning. When dosed in the evening, the DRV Cmax, AUC and Ctrough were 0.79 (0.70-0.90), 1.34 (1.25-1.43), and 0.54 (0.48-0.62), respectively. When dosed twice daily, the DRV Cmax, AUC and Ctrough were 0.87 (0.79-0.96), 0.80 (0.74-0.86) and 0.57 (0.48-0.67), respectively.
LSM ratios (90% CI) for the 3D regimen coadministered with DRV dosed in the morning were as follows:
Cmax, AUC and Ctrough for paritaprevir were 1.54 (1.14-2.09), 1.29 (1.04-1.61) and 1.30 (1.09-1.54) respectively. Those for ritonavir were 0.84 (0.72-0.98), 0.85 (0.78-0.93) and 1.07 (0.93-1.23). Those for ombitasvir were 0.86 (0.77-0.95), 0.86 (0.79-0.94) and 0.87 (0.82-0.92). Those for dasabuvir were 1.10 (0.88-1.37), 0.94 (0.78-1.14) and 0.90 (0.76-1.06) respectively.
LSM ratios (90% CI) for the 3D regimen with evening dosing of boosted DRV were as follows:
Cmax, AUC and Ctrough for paritaprevir were 0.70 (0.50-0.99), 0.81 (0.60-1.09) and 1.59 (1.23-2.05). Those for ritonavir were 1.19 (1.06-1.33), 1.70 (1.54-1.88) and 14.15 (11.66-17.18) respectively. Those for ombitasvir were 0.87 (0.82-0.93), 0.87 (0.81-0.93) and 0.87 (0.80-0.95). And those for dasabuvir were 0.75 (0.64-0.88), 0.72 (0.64-0.82) and 0.65 (0.58-0.72), respectively.
LSM ratios (90% CI) for the 3D regimen with twice-daily boosted DRV were as follows:
Cmax, AUC and Ctrough for paritaprevir were 0.70 (0.43-1.12), 0.59 (0.44-0.79) and 0.83 (0.69-1.01) respectively. Those for ritonavir were not evaluated. Those for ombitasvir were 0.76 (0.65-0.88), 0.73 (0.66-0.80) and 0.73 (0.64-0.83). And those for dasabuvir were 0.84 (0.67-1.05), 0.73 (0.62-0.86) and 0.54 (0.49-0.61), respectively.
Grade 2 ALT elevation was observed in 1 subject but this did not lead to study discontinuation.
The authors used information from phase 2 studies to determine that an increase in exposure by 100% or a decrease by 50% in the 3D regimen would not affect safety or efficacy of the regimen.
Study Conclusions
In the Viekira prescribing information the combination of DRV/r and Viekira Pak is not recommended.
However, in the study by Khatri, et al no dose adjustment is recommended with the combination of 3D and DRV/r Qam or BID.
In the Phase III studies, ODIN and ARTEMIS, the median DRV Ctrough was about 37-fold higher than the EC50 of the wild-type virus. Hence, during coadministration with the DAA+RBV therapy, DRV C24 from the DRV 800mg + RTV 100mg QD regimen is expected to be ~18-fold higher, while DRV C12 and C24 from the DRV 600mg + RTV 100mg BID regimen are expected to be ~18-fold and ~33-fold higher, respectively, than the EC50 of the wild-type virus.
DRV 600mg BID with ritonavir dosed separately only with the PM dose of DRV since the AM dose of DRV is boosted by the RTV coformulated with ABT-450 and ABT-267.
References
Ruane P, Adeyemi O, Trinh R, Lalezari J, Bhatt L, Slim J. Turquoise-i study: use of ombitasvir/paritaprevir/ritonavir+ dasabuvir+ ribavirin in patients with hcv/hiv-1 co-infection on stable darunavir-containing antiretroviral therapy [abstract lbps7/1]. European Aids Clinical Society Conference . Barcelona, Spain. 15; October 2015.
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