scholarly journals Pharmacokinetic Interactions between the Hepatitis C Virus Inhibitors Elbasvir and Grazoprevir and HIV Protease Inhibitors Ritonavir, Atazanavir, Lopinavir, and Darunavir in Healthy Volunteers

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Hwa-Ping Feng ◽  
Luzelena Caro ◽  
Christine Fandozzi ◽  
Xiaoyan Chu ◽  
Zifang Guo ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
Nonstructural Protein ◽  
Phase 1 ◽  
Geometric Mean ◽  
Hiv Treatment ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Pharmacokinetic Interactions

ABSTRACT The combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three phase 1 trials. Drug-drug interaction trials with healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (n = 10) and the potential two-way pharmacokinetic interactions of elbasvir (n = 30) or grazoprevir (n = 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure; the geometric mean ratio (GMR) for grazoprevir plus ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24 h (AUC0–24) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for grazoprevir AUC0–24 of 10.58 (90% CI, 7.78 to 14.39), 12.86 (90% CI, 10.25 to 16.13), and 7.50 (90% CI, 5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for elbasvir AUC0–24 of 4.76 (90% CI, 4.07 to 5.56), 3.71 (90% CI, 3.05 to 4.53), and 1.66 (90% CI, 1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir-grazoprevir with atazanavir-ritonavir, lopinavir-ritonavir, or darunavir-ritonavir is contraindicated, owing to an increase in grazoprevir exposure. Therefore, HIV treatment regimens without HIV protease inhibitors should be considered for HCV/HIV-coinfected individuals who are being treated with elbasvir-grazoprevir.

Drug-Drug Interactions of Glecaprevir and Pibrentasvir Coadministered With Human Immunodeficiency Virus Antiretrovirals

2019 ◽  
Vol 221 (2) ◽  
pp. 223-231 ◽  
Author(s):  
Matthew P Kosloski ◽  
Rajneet Oberoi ◽  
Stanley Wang ◽  
Rolando M Viani ◽  
Armen Asatryan ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Protease Inhibitors ◽  
Drug Exposure ◽  
Phase 1 ◽  
Area Under The Curve ◽  
Careful Consideration ◽  
Hiv Protease ◽  
Fixed Dose ◽  
Hiv Protease Inhibitors ◽  
Clinically Significant

Abstract Background Treatment of patients coinfected with hepatitis C and human immunodeficiency viruses (HCV; HIV) requires careful consideration of potential drug-drug interactions between HCV direct-acting antiviral agents (DAA) and HIV antiretrovirals. Glecaprevir/pibrentasvir is a fixed-dose combination of an NS3/4A protease inhibitor and an NS5A inhibitor approved for the treatment of chronic HCV genotype 1–6 infection, including patients with HIV coinfection. Methods A series of phase 1 studies was conducted to evaluate potential interactions of glecaprevir and pibrentasvir with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, abacavir/dolutegravir/lamivudine, raltegravir, rilpivirine, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, or efavirenz/emtricitabine/tenofovir disoproxil fumarate. Pharmacokinetics of the antiretrovirals and DAAs were characterized when administered alone and in combination to quantify changes in systemic drug exposure. Results Glecaprevir area under the curve increased >4-fold in the presence of ritonavir-boosted HIV protease inhibitors, while pibrentasvir concentrations were not significantly affected; elevations in alanine transaminase occurred in combination with atazanavir/ritonavir only. Exposures of glecaprevir and pibrentasvir may be significantly decreased by efavirenz. Coadministration with glecaprevir and pibrentasvir did not result in clinically significant changes in the exposure of any antiretroviral agents. Conclusions Atazanavir is contraindicated with glecaprevir/pibrentasvir and use of boosted protease inhibitors or efavirenz is not recommended. No clinically significant interactions were observed with other studied antiretrovirals.

scholarly journals Pharmacokinetic/Pharmacodynamic Predictors of Clinical Potency for Hepatitis C Virus Nonnucleoside Polymerase and Protease Inhibitors

2012 ◽  
Vol 56 (6) ◽  
pp. 3144-3156 ◽  
Author(s):  
Micaela B. Reddy ◽  
Peter N. Morcos ◽  
Sophie Le Pogam ◽  
Ying Ou ◽  
Karl Frank ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
Phase 1 ◽  
Viral Kinetics ◽  
Liver Uptake ◽  
Drug Classes ◽  
Preclinical Species ◽  
Chronic Hcv

ABSTRACTThis analysis was conducted to determine whether the hepatitis C virus (HCV) viral kinetics (VK) model can predict viral load (VL) decreases for nonnucleoside polymerase inhibitors (NNPolIs) and protease inhibitors (PIs) after 3-day monotherapy studies of patients infected with genotype 1 chronic HCV. This analysis includes data for 8 NNPolIs and 14 PIs, including VL decreases from 3-day monotherapy, total plasma trough concentrations on day 3 (Cmin), replicon data (50% effective concentration [EC50] and protein-shifted EC50[EC50,PS]), and for PIs, liver-to-plasma ratios (LPRs) measuredin vivoin preclinical species. VK model simulations suggested that achieving additional log10VL decreases greater than one required 10-fold increases in theCmin. NNPolI and PI data further supported this result. The VK model was successfully used to predict VL decreases in 3-day monotherapy for NNPolIs based on the EC50,PSand the day 3Cmin. For PIs, however, predicting VL decreases using the same model and the EC50,PSand day 3Cminwas not successful; a model including LPR values and the EC50instead of the EC50,PSprovided a better prediction of VL decrease. These results are useful for designing phase 1 monotherapy studies for NNPolIs and PIs by clarifying factors driving VL decreases, such as the day 3Cminand the EC50,PSfor NNPolIs or the EC50and LPR for PIs. This work provides a framework for understanding the pharmacokinetic/pharmacodynamic relationship for other HCV drug classes. The availability of mechanistic data on processes driving the target concentration, such as liver uptake transporters, should help to improve the predictive power of the approach.

scholarly journals Selection and Characterization of Hepatitis C Virus Replicons Dually Resistant to the Polymerase and Protease Inhibitors HCV-796 and Boceprevir (SCH 503034)

2008 ◽  
Vol 53 (2) ◽  
pp. 401-411 ◽  
Author(s):  
Mike Flint ◽  
Stanley Mullen ◽  
Anne M. Deatly ◽  
Wei Chen ◽  
Lynn Z. Miller ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Serine Protease ◽  
Protease Inhibitors ◽  
Nonstructural Protein ◽  
Pegylated Interferon ◽  
Replicative Capacity ◽  
Hsp90 Inhibitors ◽  
Ns5b Polymerase

ABSTRACT HCV-796 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase, and boceprevir is an inhibitor of the NS3 serine protease. The emergence of replicon variants resistant to the combination of HCV-796 and boceprevir was evaluated. Combining the inhibitors greatly reduced the frequency with which resistant colonies arose; however, some resistant replicon cells could be isolated by the use of low inhibitor concentrations. These replicons were approximately 1,000-fold less susceptible to HCV-796 and 9-fold less susceptible to boceprevir. They also exhibited resistance to anthranilate nonnucleoside inhibitors of NS5B but were fully sensitive to inhibitors of different mechanisms: a pyranoindole, Hsp90 inhibitors, an NS5B nucleoside inhibitor, and pegylated interferon (Peg-IFN). The replicon was cleared from the combination-resistant cells by extended treatment with Peg-IFN. Mutations known to confer resistance to HCV-796 (NS5B C316Y) and boceprevir (NS3 V170A) were present in the combination-resistant replicons. These changes could be selected together and coexist in the same genome. The replicon bearing both changes exhibited reduced sensitivity to inhibition by HCV-796 and boceprevir but had a reduced replicative capacity.

Pharmacokinetic interactions between HIV-protease inhibitors in rats

1999 ◽  
Vol 20 (5) ◽  
pp. 241-247 ◽  
Author(s):  
Hirokazu Yamaji ◽  
Yasuhiro Matsumura ◽  
Yukako Yoshikawa ◽  
Kanji Takada
Keyword(s):  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Pharmacokinetic Interactions

scholarly journals Pharmacokinetic Interactions Between the Hepatitis C Virus Protease Inhibitor Boceprevir and Ritonavir-Boosted HIV-1 Protease Inhibitors Atazanavir, Darunavir, and Lopinavir

2012 ◽  
Vol 56 (5) ◽  
pp. 718-726 ◽  
Author(s):  
Ellen G. J. Hulskotte ◽  
Hwa-Ping Feng ◽  
Fengjuan Xuan ◽  
Marga G. J. A. van Zutven ◽  
Michelle A. Treitel ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Pharmacokinetic Interactions ◽  
Hiv 1
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