**The authors used data from phase 2 studies to determine that an increase in exposure by 100% or a decrease by 50% did not have a clinically meaningful effect on the safety or efficacy profile of the 3D regimen.
Drug interactions with the direct-acting antiviral combination of ombitasvir and paritaprevir-ritonavir.
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Study Design
This was a 2-period crossover study in 12 healthy subjects to evaluate drug-drug interactions between Paritaprevir/Ritonavir/Ombitasvir + Dasabuvir (ABT-450/r/ABT-267 + ABT-333, also known as 3D regimen) and pravastatin. The 3D drugs were dosed as paritaprevir/ritonavir 150/100mg QD, ombitasvir 25mg QD, and dasabuvir 400mg BID or 250mg BID (the two strengths were from two different formulations which provided similar exposures). The pravastatin dose administered was 10mg QD.
In period 1 the 3D regimen was given alone on day 1, followed by a 14-day washout period. During period 2, pravastatin was given alone on days 1-3, followed by the 3D regimen + pravastatin on days 4-17. Plasma samples for pharmacokinetic (PK) analysis of the 3D regimen were collected on day 1 in period 1, and days 4 and 17 in period 2. Those for pravastatin were collected on days 3, 4 and 17 in period 2.
Study Results
Using Least Squares Mean (LSM) ratios and corresponding 90% confidence intervals, Cmax and AUC for ombitasvir were 0.95 (0.89-1.02) and 0.94 (0.89-0.99) respectively. Those for dasabuvir were 1.00 (0.87-1.14) and 0.96 (0.85-1.09). Those for paritaprevir were 0.96 (0.69-1.32) and 1.13 (0.92-1.38). And those for ritonavir were 0.89 (0.73-1.09) and 0.95 (0.86-1.05) respectively, when these were co-administered with pravastatin.
Co-administration of pravastatin with the 3D regimen resulted in increased plasma concentrations of pravastatin. The LSM ratios and 90% CI for pravastatin Cmax and AUC were 1.37 (1.11-1.69) and 1.82 (1.60-2.08) respectively.
The authors recommend reducing the pravastatin dose by half, and the dose should not exceed 40mg per day. Monitoring is warranted when this combination is utilized.
Using Least Squares Mean (LSM) ratios and corresponding 90% confidence intervals, Cmax and AUC for ombitasvir were 0.92 (0.82-1.04) and 0.89 (0.83-0.95) respectively. Those for dasabuvir were 1.07 (0.92-1.24) and 1.08 (0.92-1.26). Those for paritaprevir were 1.59 (1.13-2.23) and 1.52 (1.23-1.90). And those for ritonavir were 0.98 (0.84-1.15) and 1.02 (0.93-1.12) respectively, when these were co-administered with rosuvastatin.
Co-administration of rosuvastatin with the 3D regimen resulted in increased plasma concentrations of rosuvastatin. The LSM ratios and 90% CI for rosuvastatin Cmax and AUC were 7.13 (5.11-9.96) and 2.59 (2.09-3.21) respectively.
Using Least Squares Mean (LSM) ratios and corresponding 90% confidence intervals, the Cmax and AUC for R-methadone were 1.04 (0.98-1.11) and 1.05 (0.98-1.11) respectively, and those for S-methadone were similar, 0.99 (0.91-1.07) and 0.99 (0.88-1.09) in the PK study.
Results from the efficacy study showed that 37 of 38 patients (97.4%; 95% CI, 92.3–100) achieved SVR12. One patient prematurely discontinued due to a serious adverse event (cerebrovascular accident) unrelated to study drug. There were no virologic failures, and no patient required a change in the dosage of methadone or buprenorphine during study treatment.
Using Least Squares Mean (LSM) ratios and corresponding 90% confidence intervals, the Cmax and AUC for buprenorphine were 2.18 (1.78-2.68) and 2.07 (1.78-2.40) respectively.
Results from the efficacy study showed that 37 of 38 patients (97.4%; 95% CI, 92.3–100) achieved SVR12. One patient prematurely discontinued due to a serious adverse event (cerebrovascular accident) unrelated to study drug. There were no virologic failures, and no patient required a change in the dosage of methadone or buprenorphine during study treatment.
No dose adjustments are required, however, monitoring of buprenorphine is warranted due to the wide confidence intervals and increased mean plasma concentrations by approximately 100%, when co-administered with the 3D regimen. Patients should be closely monitored for sedation and cognitive effects.
Study Conclusions
The authors recommend reducing the pravastatin dose by half, and the dose should not exceed 40mg per day. Monitoring is warranted when this combination is utilized.
It is recommended to decrease the rosuvastatin dose and limit the maximum rosuvastatin dose to 10mg per day. Monitoring of the therapeutic effect of rosuvastatin is recommended.
There were no virologic failures, and no patient required a change in the dosage of methadone or buprenorphine during study treatment.
References
Badri PS, Dutta S, Wang H, Podsadecki TJ, Polepally AR, Khatri A, Menon RM. Drug interactions with the direct-acting antiviral combination of ombitasvir and paritaprevir-ritonavir. Antimicrobial Agents And Chemotherapy . 2016; 1: 105-114.
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