Pharmacokinetic/Pharmacodynamic predictors of clinical potency for hepatitis C virus nonnucleoside polymerase and protease inhibitors
| Autor: | Patrick F. Smith, Micaela B. Reddy, Sophie Le Pogam, Peter N. Morcos, Thierry Lave, Ying Ou, Karl Frank |
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| Rok vydání: | 2012 |
| Předmět: |
Pharmacology
Protease biology medicine.medical_treatment Hepacivirus Hepatitis C virus Models Theoretical biology.organism_classification medicine.disease_cause Virology Antiviral Agents Infectious Diseases Pharmacokinetics In vivo Pharmacodynamics medicine Potency Humans Pharmacology (medical) Protease Inhibitors Experimental Therapeutics Viral load |
| Zdroj: | Antimicrobial agents and chemotherapy. 56(6) |
| ISSN: | 1098-6596 |
| Popis: | This 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 ( C min ), replicon data (50% effective concentration [EC 50 ] and protein-shifted EC 50 [EC 50,PS ]), and for PIs, liver-to-plasma ratios (LPRs) measured in vivo in preclinical species. VK model simulations suggested that achieving additional log 10 VL decreases greater than one required 10-fold increases in the C min . 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 EC 50,PS and the day 3 C min . For PIs, however, predicting VL decreases using the same model and the EC 50,PS and day 3 C min was not successful; a model including LPR values and the EC 50 instead of the EC 50,PS provided 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 3 C min and the EC 50,PS for NNPolIs or the EC 50 and 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. |
| Databáze: | OpenAIRE |
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