Dasabuvir/ombitasvir/paritaprevir/ritonavir vs efavirenz, emtricitabine/tenofovir disoproxil fumarate, or dasabuvir/ombitasvir/paritaprevir/ritonavir
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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 + dasabuvir (ABT-450/r + ABT-333, also known as 2D regimen) and efavirenz (EFV), when administered together in healthy subjects. The 2D drugs were dosed as paritaprevir/ritonavir 150/100mg QD and dasabuvir 400mg BID. EFV was administered as Atripla (efavirenz/tenofovir/emtricitabine 600/300/200 mg), given QD. In cohort 1 (n=9), the 2D regimen was given alone on day 0-14 followed by 2D regimen + Atripla on day 14-28. In cohort 2 (n=7), Atripla was given alone on day 0-14 followed by 2D regimen + Atripla on day 14-28. All doses were administered under non-fasting conditions.
Study Results
Using Least Squares Mean (LSM) ratios and 90% confidence intervals (90% CI), the Cmax, AUC and Ctrough for RPV (morning dosing) when coadministered with the 3D regimen were 2.55 (2.08-3.12), 3.25 (2.80-3.77) and 3.62 (3.12-4.21), respectively. For evening dosing, the Cmax, AUC and Ctrough for RPV were 2.16 (1.79-2.61), 2.50 (2.05-3.06) and 2.87 (2.28-3.62), respectively, and for night dosing these values were 3.00 (2.50-3.59), 3.43 (3.03-3.89) and 3.73 (3.16-4.40), respectively. The LSM ratios (90% CI) for the 3D regimen with morning dosing of RPV were as follows:The Cmax, AUC and Ctrough for paritaprevir were 1.30 (0.94-1.81), 1.23 (0.93-1.64) and 0.95 (0.84-1.07), respectively. Those for ritonavir were 1.10 (0.98-1.24), 1.08 (0.93-1.27) and 0.97 (0.91-1.04). Those for ombitasvir were 1.11 (1.02-1.20), 1.09 (1.04-1.14) and 1.05 (1.01-1.08). Those for dasabuvir were 1.18 (1.02-1.37), 1.17 (0.99-1.38) and 1.10 (0.89-1.37), respectively.The LSM ratios (90% CI) for the 3D regimen with evening dosing of RPV were as follows:The Cmax, AUC and Ctrough for paritaprevir were 1.22 (0.96-1.55), 1.19 (0.92-1.53) and 1.24 (0.90-1.71). Those for ritonavir were 0.95 (0.82-1.09), 0.96 (0.84-1.10) and 0.99 (0.85-1.16), respectively. Those for ombitasvir were 1.06 (1.00-1.13), 1.05 (0.99-1.12) and 1.06 (1.00-1.13). And those for dasabuvir were 1.06 (0.90-1.24), 1.07 (0.96-1.20) and 1.04 (0.96-1.12), respectively.The LSM ratios (90% CI) for the 3D regimen with night time (4 hrs after dinner) dosing of RPV were as follows:The Cmax, AUC and Ctrough for paritaprevir were 0.80 (0.58-1.09), 0.83 (0.63-1.10) and 0.96 (0.68-1.35), respectively. Those for ritonavir were 0.88 (0.70-1.12), 0.89 (0.78-1.01) and 0.93 (0.76-1.14), respectively. Those for ombitasvir were 0.96 (0.89-1.05), 0.94 (0.88-1.00) and 0.96 (0.89-1.03). And those for dasabuvir were 0.96 (0.81-1.12), 0.97 (0.86-1.09) and 0.94 (0.82-1.08), respectively.2 out of 60 subjects discontinued prematurely due to adverse events, and one subject was discontinued based on investigator's discretion.
Study Conclusions
Based on increased exposures of RPV (increase of mean AUC by 150-243%) when coadministered with the 3D regimen, utilization of this drug combination is not recommended due to the risk of QTc prolongation.
References
A Khatri, T Wang, H Wang, et al. Drug-drug interactions of the direct acting antiviral regimen of abt-450/r, ombitasvir, and dasabuvir with emtricitabine tenofovir, raltegravir, rilpivirine and efavirenz. 54th Interscience Conference On Antimicrobial Agents And Chemotherapy. Washington, DC. ; 2014.
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