2008
DOI: 10.1124/dmd.107.019711
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Abstract: ABSTRACT:(R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine (PF02341066) was identified as an orally available, ATP-competitive small molecule inhibitor of cMet receptor tyrosine kinase. The objectives of the present studies were to characterize 1) the pharmacokinetic-pharmacodynamic relationship of the plasma concentrations of PF02341066 to cMet phosphorylation in tumor (biomarker) and 2) the relationship of cMet phosphorylation to antitumor efficacy (pharma… Show more

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Cited by 91 publications
(108 citation statements)
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“…The IDR model used here assumes that the rate of the onset and offset of the pEGFR levels is governed by the indirect mechanism of action, ie, inhibition of formation (K in ), because erlotinib blocks the formation of pEGFR. The model reasonably described the PK/PD relationship of the plasma concentration and pEGFR inhibition as well as provided the best fit to the observed biomarker data other than the effect compartment model (data not shown), the latter model is usually used to describe the delayed response due to delayed drug distribution [13,27] .…”
Section: Discussionmentioning
confidence: 99%
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“…The IDR model used here assumes that the rate of the onset and offset of the pEGFR levels is governed by the indirect mechanism of action, ie, inhibition of formation (K in ), because erlotinib blocks the formation of pEGFR. The model reasonably described the PK/PD relationship of the plasma concentration and pEGFR inhibition as well as provided the best fit to the observed biomarker data other than the effect compartment model (data not shown), the latter model is usually used to describe the delayed response due to delayed drug distribution [13,27] .…”
Section: Discussionmentioning
confidence: 99%
“…One study previously reported that treatment with PF02341066, a cMet kinase inhibitor, and monitoring cMet as a biomarker showed that the EC 90 for inhibiting cMet phosphorylation was as same as the EC 50 for tumor growth inhibition, suggesting that 90% inhibition of cMet is required for 50% tumor growth inhibition [13] . A similar study on PF04942847, an HSP90 inhibitor, that used Akt as a biomarker showed that 30% inhibition of Akt is required for 50% tumor growth inhibition [27] .…”
Section: Discussionmentioning
confidence: 99%
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“…To quantitatively investigate the relationship between the plasma concentration of TM208 and tumor pEGFR levels, an indirect response PD model was developed. This model describes the delayed response more adequately than the effect compartment model [28,33] . In this model, we assumed that TM208 affects pEGFR levels through an indirect PD effect, diminishing the formation rate of pEGFR, ie, parameter k in (1.9 h -1 ).…”
Section: Discussionmentioning
confidence: 99%
“…While some models (e.g. [7]) directly incorporate the effect of drugs (making them at least semi-mechanistic), now the same -empirical -growth model is assumed to apply in both the control and the treated groups; the drug exerts its effects by altering the parameters of the curve.…”
Section: Tumor Growth Modelsmentioning
confidence: 99%