当前位置： SCI文献检索 > BRITISH JOURNAL OF CLINICAL PHARMACOLOGY期刊下所有文献 > Use of modelling and simulation techniques to support decision making on the progression of PF-04878691, a TLR7 agonist being developed for hepatitis C.

Use of modelling and simulation techniques to support decision making on the progression of PF-04878691, a TLR7 agonist being developed for hepatitis C.

Abstract：

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.

journal_name

Br J Clin Pharmacol

journal_title

British journal of clinical pharmacology

authors

Jones HM,Chan PL,van der Graaf PH,Webster R

doi

10.1111/j.1365-2125.2011.04047.x

subject

Has Abstract

pub_date

2012-01-01 00:00:00

pages

77-92

issue

eissn

0306-5251

issn

1365-2125

journal_volume

pub_type

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Use of modelling and simulation techniques to support decision making on the progression of PF-04878691, a TLR7 agonist being developed for hepatitis C.