Exposure-Response Analysis for Efficacy of Daclatasvir, Asunaprevir, and Beclabuvir Combinations in HCV-Infected Patients.

Abstract

The combination regimen of daclatasvir, asunaprevir, and beclabuvir (3DAA regimen) was developed as a fixed-dose combination for the treatment of hepatitis C virus (HCV) infection in Japan. The objectives of this analysis were to characterize the relationship between drug exposure and sustained virologic response at posttreatment week 12 (SVR12) in HCV-infected subjects and to evaluate the impact of demographic covariates and clinical factors on the exposure-response (E-R) relationship. The E-R efficacy analysis was performed with data from phase 2 and phase 3 studies in HCV-infected subjects treated with the 3DAA regimen. The relationship between the probability of achieving SVR12 and exposure to daclatasvir, asunaprevir, and beclabuvir was described using a logistic regression model and included assessments of the potential covariate effects. The impacts of the covariates on the rate of SVR12 and interactions of covariates with the individual drug effects were tested. The final model for SVR12 included effects of non-genotype-1a status, resistance-associated NS5A-Q30 substitution in genotype-1a subjects, and baseline RNA level on the intercept, and effect of prior peg-interferon failure on the beclabuvir slope. Sex, race, age, weight, fibrosis score, alanine transaminase, and cirrhosis status had no statistically significant impact on the rate of SVR12. The individual E-R relationships with each drug, were relatively flat, and the effects of exposure were not significant. With the exception of the NS5A-Q30 substitution in genotype-1a subjects, statistically significant covariate effects had little impact on SVR12 rates. Overall, the E-R model was developed that captured the high SVR12 rates and the effect of covariates for the 3DAA regimen in HCV-infected patients.

• Authors: T Ueno, M Osawa, T Shiozaki, M Green, T Garimella
• Journal: Clinical pharmacology in drug development (Clin Pharmacol Drug Dev) Vol. 8 Issue 7 Pg. 903-913 (10 2019) ISSN: 2160-7648 [Electronic] United States
• PMID: 30667592 (Publication Type: Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019, The American College of Clinical Pharmacology.

Chemical References

• 8-cyclohexyl-N-((dimethylamino)sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-((3-methyl-3,8-diazabicyclo(3.2.1)oct-8-yl)carbonyl)cycloprop(d)indolo(2,1-a)(2)benzazepine-5-carboxamide
• Benzazepines
• Carbamates
• Drug Combinations
• Imidazoles
• Indoles
• Isoquinolines
• Pyrrolidines
• Sulfonamides
• Viral Nonstructural Proteins
• NS-5 protein, hepatitis C virus
• Valine
• daclatasvir
• asunaprevir

Topics

• Adult
• Aged
• Amino Acid Substitution
• Benzazepines (administration & dosage, pharmacology)
• Carbamates
• Drug Combinations
• Female
• Hepacivirus (drug effects, genetics)
• Hepatitis C (drug therapy, virology)
• Humans
• Imidazoles (administration & dosage, pharmacology)
• Indoles (administration & dosage, pharmacology)
• Isoquinolines (administration & dosage, pharmacology)
• Logistic Models
• Male
• Middle Aged
• Pyrrolidines
• Sulfonamides (administration & dosage, pharmacology)
• Sustained Virologic Response
• Treatment Outcome
• Valine (analogs & derivatives)
• Viral Nonstructural Proteins (genetics)