HCV Model Development: Industry Perspective. Larissa Wenning Quantitative Translational Models to Accelerate Hepatitis C Drug Development August 2, 2012. What Do We Want From HCV Models?. OUTPUTS. INPUTS. Data. Portable, integrated form of knowledge. Clearly Defined Assumptions.
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Quantitative Translational Models to Accelerate Hepatitis C Drug Development
August 2, 2012
Portable, integrated form of knowledge
Exploration of Knowledge
Integrated, mathematical representation of all inputs
Ideas & Scientific
Predictions vs. Observations
Core viral dynamics model with clear separation between parameters associated with the biological system (virus, hepatocytes), and those associated with the drug; can “plug and play” parameter sets to simulate combinations of drugs in different populations of interest
Drug effect only on production of virus
Not shown in diagram,
but RBV treatment assumed to result in production of non-infectious virus, which also decays at rate c; then measured total virus = infectious + non-infectious
Total # of hepatocytes assumed to remain constant (T0)
Model applied to several compounds: MK-5172, MK-7009, Peg-IFN, RBV, boceprevir, etc
Poland et al, American Conference of Pharmacometrics, San Diego, CA, April 2011.
Illustrative example showing fit to 3 individual subjects in an MK-7009 Phase II study (MK-7009+PR x 4 wks followed by PR x 44 wks):
Example: Simulated MK-7009 Dose-Response with PR in Treatment-Naïve Patients
MK-7009+PR through treatment period
Nachbar et al., EASL 2012 & 7th International Workshop on Hepatitis C Resistance & New Compounds
Dose differentiation for GT1 predicted to be at or below 10 mg
50 mg dose for GT3 predicted to be no different than placebo
Very high percentage of patients are expected to become undetectable quickly, and remain so while on therapy