ARIAD Pharmaceuticals Message Board

To: bellweather who wrote (1901)	5/11/2012 11:48:25 AM
From: Biomaven	of 2622

I'm not aware of any data relating to what degree Erlotinib's efficacy relates to its inhibition of wild-type EGFR. No real way to study that issue without a drug that only inhibits mutated EGFR. In ARIA's discussion of '113, they said that it inhibits both mutated EGFR and activated EGFR. It's not clear if that means activation because of some mutation or activation of wild-type because the ligand is present. FWIW, erlotinib is significantly more active against some mutated EGFR than against wild-type: Wild-type EGFR was inhibited by 50 percent at a gefitinib concentration of 0.1 µM and was completely inhibited by a concentration of 2.0 µM, whereas the respective values for the two mutant proteins were 0.015 µM and 0.2 µM ( Figure 3C and Figure 3D). This difference in drug sensitivity may be clinically relevant, since pharmacokinetic studies indicate that daily oral administration of 400 to 600 mg of gefitinib results in a mean steady-state trough plasma concentration of 1.1 to 1.4 µM, whereas the currently recommended daily dose of 250 mg leads to a mean trough concentration of 0.4 µM. 21 nejm.org Peter