(actually, handicapping this ISEL result is an interesting exercise)
The underlying assumption is that both molecules are metabolized at the same maximum catalytic rate by the cytochrome enzymes involved... therefore, the only variable influencing overall clearance of the two drugs is total enzyme activity. Both Iressa and Tarceva are cleared primarily by Cyp3A4 and additionally by Cyp1A2. The latter, Cyp1A2, is induced by smoking. Therefore, clearance in smokers should proceed at a faster rate assuming that clearance is proportional to the sum of the total activities of Cyp3A4 and Cyp1A2. Since Iressa is less potent, and maintains lower Cmax and Css values than Tarceva, the clearance of both drugs under conditions of normal Cyp3A4 and Cyp1A2 activity should give Tarceva the edge. With Cyp1A2 induction in smokers, the overall clearance for both drugs (dictated by Cyp3aA4 + Cyp1A2 activities) should increase, giving an additional neck-up for Tarceva in the PK/PD race.
All theoretical, mind you... but if ISEL fails to match BR21, I'm going to pretend as if the above explanation was the clincher ;-)
Some interesting Iressa data from the Moffitt cancer centre that I had not previously seen:
They ran their own prospective Iressa study in 183 patients. The population is about 50% adeno, but did not restrict enrollment to those having previously received chemo. 18% were chemo naive, 40% had received 1 prior therapy. Most were PS0-1 (32%:43%), and 7.7% were PS3. Generally a healthier population than in the BR21 study. Nice data to have handy for those handicapping the Iressa versus Tarceva battle.
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