Use of modelling and simulation techniques to support decision making on the progression of PF-04878691, a TLR7 agonist being developed for hepatitis C
Article first published online: 8 DEC 2011
© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 73, Issue 1, pages 77–92, January 2012
How to Cite
Jones, H. M., Chan, P. L. S., van der Graaf, P. H. and Webster, R. (2012), Use of modelling and simulation techniques to support decision making on the progression of PF-04878691, a TLR7 agonist being developed for hepatitis C. British Journal of Clinical Pharmacology, 73: 77–92. doi: 10.1111/j.1365-2125.2011.04047.x
- Issue published online: 8 DEC 2011
- Article first published online: 8 DEC 2011
- Accepted manuscript online: 20 JUN 2011 11:02PM EST
- Received; 5 April 2011; Accepted; 12 June 2011; Accepted Article; 20 June 2011
- population modelling;
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• While several clinical studies have been published on toll-like receptor 7 (TLR7) agonists, there is no information on the quantitative link between 2′,5′-oligoadenylate synthetase (OAS) and antiviral efficacy (viral load).
WHAT THIS STUDY ADDS
• This study provides the only quantitative dynamic clinical relationship between the pharmacokinetics (PK) of PF-04878691 and OAS and lymphocyte levels, together with the only published clinical relationship between markers of anti-viral pharmacology (OAS) and antiviral efficacy (viral load). This study highlights how modelling and simulation can be used to impact compound progression decisions in clinical development.
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.
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.
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.
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.