| Autor: |
Haseltine EL; Vertex Pharmaceuticals Incorporated, 50 Northern Ave., Boston, MA, 02210, United States. eric_haseltine@vrtx.com., Kimko H; Janssen Research & Development, Raritan, NJ, United States., Luo H; RES Group, Cambridge, MA, United States., Tolsma J; RES Group, Cambridge, MA, United States., Bartels DJ; Vertex Pharmaceuticals Incorporated, 50 Northern Ave., Boston, MA, 02210, United States., Kieffer TL; Vertex Pharmaceuticals Incorporated, 50 Northern Ave., Boston, MA, 02210, United States., Garg V; Vertex Pharmaceuticals Incorporated, 50 Northern Ave., Boston, MA, 02210, United States. |
| Abstrakt: |
Viral dynamic modelling has proven useful for designing clinical studies and predicting treatment outcomes for patients infected with the hepatitis C virus. Generally these models aim to capture and predict the on-treatment viral load dynamics from a small study of individual patients. Here, we explored extending these models (1) to clinical studies with numerous patients and (2) by incorporating additional data types, including sequence data and prior response to interferon. Data from Phase 3 clinical studies of the direct-acting antiviral telaprevir (T; total daily dose of 2250 mg) combined with pegylated-interferon alfa and ribavirin (PR) were used for the analysis. The following data in the treatment-naïve population were reserved to verify the model: (1) a T/PR regimen where T was dosed every 8 h for 8 weeks (T8(q8h)/PR) and (2) a T/PR regimen where T was dosed twice daily for 12 weeks (T12(b.i.d.)/PR). The resulting model accurately predicted (1) sustained virologic response rates for both of these dosing regimens and (2) viral breakthrough characteristics of the T8(q8h)/PR regimen. Since the observed viral variants depend on the T exposure, the second verification suggested that the model was correctly sensitive to the different T regimen even though the model was developed using data from another T regimen. Furthermore, the model predicted that b.i.d. T dosing was comparable to q8h T dosing in the PR-experienced population, a comparison that has not been made in a controlled clinical study. The methods developed in this work to estimate the variability occurring below the limit of detection for the viral load were critical for making accurate predictions. |
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