Population pharmacokinetics of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin in hepatitis C virus genotype 1 infection: analysis of six phase III trials
| Autor: | Walid M. Awni, Amit Khatri, Thomas Podsadecki, Doerthe Eckert, Sven Mensing, Akshanth R. Polepally, Sandeep Dutta, Rajeev M. Menon, Shringi Sharma |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty 030106 microbiology Population Pharmacology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine Medicine Pharmacology (medical) 030212 general & internal medicine education education.field_of_study Dasabuvir business.industry Ribavirin virus diseases Ombitasvir NONMEM Regimen chemistry Paritaprevir Ritonavir business medicine.drug |
| Zdroj: | British Journal of Clinical Pharmacology. 83:527-539 |
| ISSN: | 0306-5251 |
| Popis: | Aim To characterize the population pharmacokinetics of a triple direct-acting antiviral (DAA) regimen (3D) (ombitasvir, paritaprevir-ritonavir, and dasabuvir) and adjunctive ribavirin and estimate covariate effects in a broad spectrum of subjects with hepatitis C virus (HCV) genotype 1 infection. Methods Pharmacokinetic data from six phase 3 studies and one phase 2 study in subjects receiving the currently approved doses of the 3D ± ribavirin regimen for treating HCV genotype 1 infection for 12 or 24 weeks were characterized using separate population pharmacokinetic models built using each component of the regimen from non-linear mixed-effects methodology in NONMEM 7.3. In the models, demographic and clinical covariates were tested. Models were assessed via goodness-of-fit plots, visual predictive checks, and bootstrap evaluations. Results The population pharmacokinetic models for each component of the 3D ± ribavirin regimen (DAAs and ritonavir, N = 2348) and ribavirin (N = 1841) adequately described their respective plasma-concentration-time data. Model parameter estimates were precise and robust, and all models showed good predictive performance. Significant covariate effects associated with apparent clearance and volume of distribution included age, body weight, sex, cirrhosis, HCV subtype, opioid or antidiabetic agent use, and creatinine clearance. Conclusion Population pharmacokinetics of the 3D ± ribavirin regimen components in HCV-infected patients were characterized using phase 3 and 2 HCV clinical trial data. Although several statistically significant covariates were identified, their effects were modest and not clinically meaningful to necessitate dose adjustments for any component of the 3D regimen. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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