AIM: To use non-linear mixed effects modelling and simulation techniques to predict whether PF-04878691, a toll-like receptor 7 (TLR7) agonist, would produce sufficient antiviral efficacy while maintaining an acceptable side effect profile in a 'proof of concept' (POC) study in chronic hepatitis C (HCV) patients. METHODS: A population pharmacokinetic-pharmacodynamic (PKPD) model was developed using available 'proof of pharmacology' (POP) clinical data to describe PF-04878691 pharmacokinetics (PK) and its relationship to 2',5'-oligoadenylate synthetase (OAS; marker of pharmacology) and lymphocyte levels (marker of safety) following multiple doses in healthy subjects. A second model was developed to describe the relationship between change from baseline OAS expressed as fold change and HCV viral RNA concentrations using clinical data available in HCV patients for a separate compound, CPG-10101 (ACTILON™), a TLR9 agonist. Using these models the antiviral efficacy and safety profiles of PF-04878691 were predicted in HCV patients. RESULTS: The population PKPD models described well the clinical data as assessed by visual inspection of diagnostic plots, visual predictive checks and precision of the parameter estimates. Using these relationships, PF-04878691 exposure and HCV viral RNA concentration was simulated in HCV patients receiving twice weekly administration for 4 weeks over a range of doses. The simulations indicated that significant reductions in HCV viral RNA concentrations would be expected at doses > 6 mg. However at these doses grade ≥ 3 lymphopenia was also predicted. CONCLUSIONS: The model simulations indicate that PF-04878691 is unlikely to achieve POC criteria and support the discontinuation of this compound for the treatment of HCV.
AIM: To use non-linear mixed effects modelling and simulation techniques to predict whether PF-04878691, a toll-like receptor 7 (TLR7) agonist, would produce sufficient antiviral efficacy while maintaining an acceptable side effect profile in a 'proof of concept' (POC) study in chronic hepatitis C (HCV) patients. METHODS: A population pharmacokinetic-pharmacodynamic (PKPD) model was developed using available 'proof of pharmacology' (POP) clinical data to describe PF-04878691 pharmacokinetics (PK) and its relationship to 2',5'-oligoadenylate synthetase (OAS; marker of pharmacology) and lymphocyte levels (marker of safety) following multiple doses in healthy subjects. A second model was developed to describe the relationship between change from baseline OAS expressed as fold change and HCV viral RNA concentrations using clinical data available in HCV patients for a separate compound, CPG-10101 (ACTILON™), a TLR9 agonist. Using these models the antiviral efficacy and safety profiles of PF-04878691 were predicted in HCV patients. RESULTS: The population PKPD models described well the clinical data as assessed by visual inspection of diagnostic plots, visual predictive checks and precision of the parameter estimates. Using these relationships, PF-04878691 exposure and HCV viral RNA concentration was simulated in HCV patients receiving twice weekly administration for 4 weeks over a range of doses. The simulations indicated that significant reductions in HCV viral RNA concentrations would be expected at doses > 6 mg. However at these doses grade ≥ 3 lymphopenia was also predicted. CONCLUSIONS: The model simulations indicate that PF-04878691 is unlikely to achieve POC criteria and support the discontinuation of this compound for the treatment of HCV.
Authors: Martin Lagging; Ana I Romero; Johan Westin; Gunnar Norkrans; Amar P Dhillon; Jean-Michel Pawlotsky; Stefan Zeuzem; Michael von Wagner; Francesco Negro; Solko W Schalm; Bart L Haagmans; Carlo Ferrari; Gabriele Missale; Avidan U Neumann; Elke Verheij-Hart; Kristoffer Hellstrand Journal: Hepatology Date: 2006-12 Impact factor: 17.425
Authors: Gregory L Armstrong; Annemarie Wasley; Edgar P Simard; Geraldine M McQuillan; Wendi L Kuhnert; Miriam J Alter Journal: Ann Intern Med Date: 2006-05-16 Impact factor: 25.391
Authors: D Goldstein; P Hertzog; E Tomkinson; D Couldwell; S McCarville; S Parrish; P Cunningham; M Newell; M Owens; D A Cooper Journal: J Infect Dis Date: 1998-09 Impact factor: 5.226
Authors: Mira C Patel; Kari Ann Shirey; Lioubov M Pletneva; Marina S Boukhvalova; Alfredo Garzino-Demo; Stefanie N Vogel; Jorge Cg Blanco Journal: Future Virol Date: 2014-09 Impact factor: 1.831