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 effect safety or efficacy of the regimen. Caution is still warranted due to wide confidence intervals
Key drug–drug interactions with direct-acting antiviral in HIV–HCV coinfection
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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 atazanavir (ATV), 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. ATV was administered as 300mg QD in the morning (n=24)or in the evening (n=24) with 100mg ritonavir only in the evening. Ritonavir was only given with the evening doses of ATV since the 3D regimen provided ritonavir for the morning doses.
Blood samples for pharmacokinetic (PK) analysis were collected following dosing of 3D regimen alone, boosted ATV alone, and the combination of the two.
Study Results
Using Least Squares Mean (LSM) ratios and 90% confidence intervals (CI), Cmax, AUC and Ctrough for ATV when coadministered with the 3D regimen were 0.91 (0.84-0.99), 1.01 (0.93-1.10) and 0.90 (0.81-1.01) respectively, when dosed in the morning. When dosed in the evening, ATV Cmax, AUC and Ctrough were 1.02 (0.92-1.13), 1.19 (1.11-1.28), and 1.68 (1.44-1.95) respectively.
LSM ratios (90% CI) for the 3D regimen coadministered with ATV dosed in the morning were as follows:
Cmax, AUC and Ctrough for paritaprevir were 1.46 (1.06-1.99), 1.94 (1.34-2.81) and 3.26 (2.06-5.16) respectively. Those for ritonavir were 0.88 (0.77-1.01), 0.95 (0.84-1.08) and 1.40 (1.15-1.72). Those for ombitasvir were 0.77 (0.70-0.85), 0.83 (0.74-0.94) and 0.89 (0.78-1.02). Those for dasabuvir were 0.83 (0.71-0.96), 0.82 (0.71-0.94) and 0.79 (0.66-0.94) respectively.
LSM ratios (90% CI) for the 3D regimen with evening dosing of boosted ATV were as follows:
Cmax, AUC and Ctrough for paritaprevir were 2.19 (1.61-2.98), 3.16 (2.40-4.17) and 11.95 (8.94-15.98). Those for ritonavir were 1.60 (1.38-1.86), 3.18 (2.74-3.69) and 24.65 (18.64-32.6) respectively. Those for ombitasvir were 0.83 (0.72-0.96), 0.90 (0.78-1.02) and 1.00 (0.89-1.13). And those for dasabuvir were 0.81 (0.73-0.91), 0.81 (0.71-0.92) and 0.80 (0.65-0.98), respectively.
respectively.
Two subjects discontinued the study due to adverse events (1st degree AV block and macular rash and pruritis). Grade 3 total bilirubin elevation was observed in 10/24 subjects (morning ATV) and 16/24 subjects (evening ATV), but this did not lead to study discontinuation.
The authors ONLY recommend (without dose adjustment) the 3D regimen (as given in this study) with morning ATV and the ritonavir from the 3D regimen is used as the ATV boosting ritonavir (no additional ritonavir). However, caution is warranted due to the wide confidence intervals observed with increased exposure and Ctrough of paritaprevir during coadministration with ATV.
Study Conclusions
The authors ONLY recommend (without dose adjustment) the 3D regimen (as given in this study) with morning ATV and the ritonavir from the 3D regimen is used as the ATV boosting ritonavir (no additional ritonavir). However, caution is warranted due to the wide confidence intervals observed with increased exposure and Ctrough of paritaprevir during coadministration with ATV.
References
El-Sherif O, Khoo S, Solas C. Key drug–drug interactions with direct-acting antiviral in hiv–hcv coinfection. Current Opinion In Hiv And Aids. 2015; 5: 348-354.
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