803 RELATIONSHIP BETWEEN TRANSAMINASE LEVELS AND PLASMA PHARMACOKINETICS FOLLOWING ADMINISTRATION OF MK-5172 WITH PEGYLATED INTERFERON alfa-2b AND RIBAVIRIN (PR) TO HCV GENOTYPE (G) 1 TREATMENT-NAÏVE PATIENTS

Caro, Luzelena; Du, Lihong; Huang, Shenlin; Wenning, Larissa; Su, Jun-Wei; Hwang, Peggy; Valesky, Robert; Gilbert, Christopher L.; Gress, Jacqueline; Klaassen, F.; Gendrano, Isaias Noel; Brunhofer, J.; Cooreman, Michael P.; Huisman, J.; Mobashery, Niloufar

doi:10.1016/s0168-8278(13)60805-3

Cited by 9 publications

(7 citation statements)

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“…Grazoprevir is active against genotype 3 but doses of 200 mg or higher are required for optimal efficacy and these higher doses have been associated with hepatotoxicity [63]. At the approved 100 mg dose, genotype 3 is not well covered.…”

Section: Genotypementioning

confidence: 99%

Second generation direct-acting antivirals – Do we expect major improvements?

Feld

Foster

2016

Journal of Hepatology

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The rapid progress in the development of direct-acting antiviral agents for hepatitis C has allowed the vast majority of patients to receive all oral therapy that will eliminate their virus. The success of the new regimens has led many to question the need for further developments in this field. Major improvements in drugs for hepatitis C are unlikely but we predict incremental improvements in the next few years. We hope that the next generation of drugs will address the unresolved issues for patients with genotype 3 infection where current treatments are still not entirely satisfactory and we anticipate improvements in the management of patients with renal failure. Shorter duration treatments, perhaps with novel modes of action, may allow simplified 'one-dose' treatments that will greatly expand our ability to treat patients who have difficulty accessing current services and we anticipate that the clinical community will better define the patients with advanced disease who will benefit from therapy prior to liver transplantation.

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Section: Genotypementioning

confidence: 99%

Second generation direct-acting antivirals – Do we expect major improvements?

Feld

Foster

2016

Journal of Hepatology

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“…Because GZR is sensitive to OATP1B inhibition and COB is reported to be an OATP1B inhibitor, the significant increase in GZR exposure is likely due to the interplay of CYP3A and OATP1B inhibition. Elevated GZR exposures achieved at doses greater than the 100‐mg recommended clinical dose (ie, 200, 400, 800 mg once daily) in phase 2 studies have been shown to be associated with an exposure‐dependent increase in the risk of late alanine aminotransferase/aspartate aminotransferase elevation events . High GZR doses result in drug exposures that are much higher (eg, 5‐ to 70‐fold) than those achieved with the clinical dose of 100 mg once daily, because GZR has nonlinear, greater than dose‐proportional pharmacokinetics .…”

Section: Discussionmentioning

confidence: 99%

“…Elevated GZR exposures achieved at doses greater than the 100-mg recommended clinical dose (ie, 200, 400, 800 mg once daily) in phase 2 studies have been shown to be associated with an exposure-dependent increase in the risk of late alanine aminotransferase/aspartate aminotransferase elevation events. 22,23 High GZR doses result in drug exposures that are much higher (eg, 5-to 70-fold) than those achieved with the clinical dose of 100 mg once daily, because GZR has nonlinear, greater than doseproportional pharmacokinetics. 12 Increases in GZR exposure in the presence of EVG/COB/TDF/FTC (>5-fold) may therefore increase the risk of transaminase elevations and consequently lead to further liver injury in people with already impaired liver function due to HCV infection.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Interactions Between the Fixed‐Dose Combinations of Elvitegravir/Cobicistat/Tenofovir Disoproxil Fumarate/Emtricitabine and Elbasvir/Grazoprevir in Healthy Adult Participants

Feng

Guo

Fandozzi

et al. 2019

Clinical Pharm in Drug Dev

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Treatment of individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) requires careful consideration of potential drug‐drug interactions. The pharmacokinetic interaction of the HCV fixed‐dose combination treatment of elbasvir/grazoprevir (EBR/GZR) when coadministered with the fixed‐dose combination HIV treatment of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (EVG/COB/TDF/FTC) was evaluated in 22 healthy adults. In period 1, oral doses of EVG/COB/TDF/FTC (150 mg/150 mg/300 mg/200 mg) were administered once daily for 7 days. In period 2, oral doses of EBR/GZR (50 mg/100 mg) were administered once daily for 10 days. In period 3, oral doses of EVG/COB/TDF/FTC were coadministered with EBR/GZR once daily for 10 days. The pharmacokinetics of EVG/COB/TDF/FTC were not clinically meaningfully altered by concomitant EBR/GZR administration. Geometric mean ratios (90%CIs) for area under the plasma concentration‐time curve from time 0 to 24 hours (AUC0‐24) in the presence/absence of EBR/GZR were 1.1 (1.0, 1.2) for elvitegravir; 1.1 (1.0, 1.1) for emtricitabine; 1.2 (1.1, 1.2) for tenofovir; and 1.5 (1.4, 1.6) for cobicistat. In comparison, the AUC0‐24 of elbasvir was ∼2 times higher and the AUC0‐24 of grazoprevir was ∼5 times higher following concomitant administration of EVG/COB/TDF/FTC and EBR/GZR. Geometric mean ratios (90%CI) for AUC0‐24 in the presence/absence of EVG/COB/TDF/FTC were 2.2 (2.0, 2.4) for elbasvir and 5.4 (4.5, 6.4) for grazoprevir. Coadministration of EVG/COB/TDF/FTC and EBR/GZR was generally well tolerated in healthy adults in this study. Nevertheless, because of the increased GZR exposure that occurs with coadministration of EVG/COB/TDF/FTC and EBR/GZR, coadministration of this combination is not recommended in those coinfected with HIV and HCV.

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“…GZR population PK analyses demonstrated that the steady-state AUC of GZR was Ϸ5-fold higher, with an upper 90% confidence interval (CI) bound of Ϸ9-fold, in Child-Pugh class B HCVinfected participants than in noncirrhotic HCV-infected participants (assuming a 100-mg GZR dose in both populations). PK/pharmacodynamic analysis of phase 2 and 3 data from participants with HCV demonstrated that high GZR doses (i.e., 200, 400, or 800 mg QD) can result in an exposure-dependent increase in the risk of late ALT/AST elevation events (6,19). Because GZR has nonlinear, greater-than-dose-proportional PK, high GZR doses result in drug exposures that are much higher (e.g., 5-to 70-fold) than those achieved with the clinical dose of 100 mg QD.…”

Section: Discussionmentioning

confidence: 99%

“…These events were initially observed in a phase 2 dose-ranging study in participants with HCV infection who were receiving high doses of GZR (18). Additional analyses demonstrated that the risk of these ALT/AST elevations increases in a GZR exposuredependent manner (6,19). Since GZR undergoes metabolism and transport in the liver, it is possible that the pharmacokinetics (PK) of GZR may be increased in HCV-infected people with hepatic impairment, which could then lead to an increased risk of transaminitis.…”

mentioning

confidence: 99%

Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor

Caro

Wenning

Guo

et al. 2017

Antimicrob Agents Chemother

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Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic infection with hepatitis C virus (HCV) genotype 1 or 4. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multipledose GZR (200, 100, or 50 mg) in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, and in healthy matched controls (protocol MK-5172_p013; Merck & Co., Inc., Kenilworth, NJ). Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study. Participants received oral doses of GZR 200 mg (two 100-mg tablets), 100 mg (one 100-mg tablet), or 50 mg (two 25-mg tablets) once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls for each hepatic cohort. Participants with HI demonstrated higher GZR exposure than healthy matched controls and showed an increase in exposure with increasing HI severity. The steadystate GZR AUC 0 -24 (area under the concentration-time curve from 0 to 24 h) for participants with mild, moderate, or severe HI was Ϸ2-, Ϸ5-, or Ϸ12-fold higher, respectively, than that for healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated for those with moderate or severe HI (Child-Pugh class B or C), since they may have significantly increased GZR exposures that may lead to an increased risk of transaminase elevation.

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803 RELATIONSHIP BETWEEN TRANSAMINASE LEVELS AND PLASMA PHARMACOKINETICS FOLLOWING ADMINISTRATION OF MK-5172 WITH PEGYLATED INTERFERON alfa-2b AND RIBAVIRIN (PR) TO HCV GENOTYPE (G) 1 TREATMENT-NAÏVE PATIENTS

Cited by 9 publications

References 0 publications

Second generation direct-acting antivirals – Do we expect major improvements?

Second generation direct-acting antivirals – Do we expect major improvements?

Pharmacokinetic Interactions Between the Fixed‐Dose Combinations of Elvitegravir/Cobicistat/Tenofovir Disoproxil Fumarate/Emtricitabine and Elbasvir/Grazoprevir in Healthy Adult Participants

Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor

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