804 Exposure–response Analyses of Asunaprevir in Combination With Daclatasvir Peginterferon/ Ribavirin Among Patients With Genotype 1 Chronic HCV Infection: Dose Selection for Phase 3 Clinical Trials

Chan, Phyllis; Tafoya, E.; Eley, Timothy; He, Bing; Gardiner, David F.; Hughes, Eric; Schnittman, Steven M.; Bertz, Richard

doi:10.1016/s0168-8278(13)60806-5

Cited by 9 publications

(7 citation statements)

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“…ALT elevations that did occur were reversible and not associated with hepatic decompensation. This is consistent with other studies showing that ALT increases are infrequently observed with ASV given at recommended doses (100‐mg softgel capsule twice daily or 200‐mg tablet twice daily) .…”

Section: Discussionsupporting

confidence: 92%

Daclatasvir plus asunaprevir for HCV genotype 1b infection in patients with or without compensated cirrhosis: a pooled analysis

Kao

Manns

Jacobson

et al. 2016

Liver International

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Section: Discussionsupporting

confidence: 92%

Daclatasvir plus asunaprevir for HCV genotype 1b infection in patients with or without compensated cirrhosis: a pooled analysis

Kao

Manns

Jacobson

et al. 2016

Liver International

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“…Although the number of subjects with cirrhosis was limited, the difference in plasma exposure in subjects with compensated cirrhosis did not appear to be clinically meaningful, as virological outcomes in these subjects were comparable to those in subjects without cirrhosis. In Phase III studies with the DUAL regimen, only 3% of subjects had experienced Grade 3/4 AST or ALT elevations, consistent with findings from a previous exposure–response analysis that suggested minimal increase in the probability of liver safety events, with an approximate doubling of ASV AUC at the clinically relevant dose [ 25 , 26 ]. On the other hand, subjects receiving the DUAL treatment had in general reduced AST levels as a result of viral clearance.…”

Section: Discussionsupporting

confidence: 79%

Population Pharmacokinetic Analysis of Asunaprevir in Subjects with Hepatitis C Virus Infection

Zhu¹,

Li²,

Chan³

et al. 2018

Infect Dis Ther

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IntroductionAsunaprevir (ASV) is a potent, pangenotypic, twice-daily hepatitis C virus (HCV) NS3 inhibitor indicated for the treatment of chronic HCV infection.MethodsA population pharmacokinetic (PPK) model was developed using pooled ASV concentration data from 1239 HCV-infected subjects who received ASV either as part of the DUAL regimen with daclatasvir or as part of the QUAD regimen with daclatasvir and peg-interferon/ribavirin.ResultsA two-compartment model with first-order elimination from the central compartment, an induction effect on clearance, and an absorption model consisted of zero-order release followed by first-order absorption adequately described ASV PK after oral administration. A typical value for ASV clearance (CL/F) was 50.8 L/h, increasing by 43% after 2 days to a CL/F of 72.5 L/h at steady-state, likely due to auto-induction of cytochrome P450 3A4 (CYP3A4). Factors indicative of hepatic function were identified as key influential covariates on ASV exposures. Subjects with cirrhosis had an 84% increase in ASV area under the concentration time curve (AUC) and subjects with baseline aspartate aminotransferase (AST) above 78 IU/L had a 58% increase in area under the concentration time curve (AUC). Asians subjects had a 46% higher steady-state AUC relative to White/Caucasian subjects. Other significant covariates were formulation, age, and gender.ConclusionThe current PPK model provided a parsimonious description of ASV concentration data in HCV-infected subjects. Key covariates identified in the model help explain the observed variability in ASV exposures and may guide clinical use of the drug.FundingBristol-Myers Squibb.Electronic supplementary materialThe online version of this article (10.1007/s40121-018-0197-y) contains supplementary material, which is available to authorized users.

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“…This higher dose will provide additional benefit by mitigating for food effects, acid modifiers, CYP3A4 inducers, and suboptimal adherence 37. In addition, the 60 mg dose is predicted to maximise antiviral response in more difficult-to-treat populations, such as cirrhotic patients, or those with genotype 1a infection, a high baseline viral load, or a non-CC IL28B genotype 37…”

Section: Discussionmentioning

confidence: 99%

Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study

Hézode

Hirschfield

Ghesquière

et al. 2014

Gut

106

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804 Exposure–response Analyses of Asunaprevir in Combination With Daclatasvir Peginterferon/ Ribavirin Among Patients With Genotype 1 Chronic HCV Infection: Dose Selection for Phase 3 Clinical Trials

Cited by 9 publications

References 0 publications

Daclatasvir plus asunaprevir for HCV genotype 1b infection in patients with or without compensated cirrhosis: a pooled analysis

Daclatasvir plus asunaprevir for HCV genotype 1b infection in patients with or without compensated cirrhosis: a pooled analysis

Population Pharmacokinetic Analysis of Asunaprevir in Subjects with Hepatitis C Virus Infection

Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study

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