RE: PD modeling question

From:"Gobburu, Jogarao V" Subject:RE: [NMusers] PD modeling question Date:Wed, February 27, 2002 11:33 am Dear Chuanpu, I have to admit that I do not know enough about the specific case, so these are just some thoughts for your consideration. It appears from your message that your drug affects ENZyme which regulates X and that you are measuring X. Although it might be challenging to delineate the exact mechanism, in my honest opinion, we need to have a reasonable understanding of the underlying mechanism. This is essential because model selection is going to be difficult, otherwise. The two approaches you mention include: 1. having a binding component and/or ENZ turnover and 2. homeostatic mechanism. I am not sure how you can attribute the second mechanism to your observation. I would expect, the second reason would speed-up the (ENZ turn-over) offset (let us say simply, X returning to baseline). According to that, inspite of having increasing amounts of the drug in the body, the effect should be diminishing (eg: nitroglycerin). ACE inhibitors are known for their tight binding to ACE, experience from them might be helpful. Also, Gisleskog et al present a nice model that takes into account the turn-over of DHT (you migh or might not need the irreversible part of the pd model). These will be good place to start (if you have not considered them already). Ref1. Toutain PL, Lefebvre HP, King JN. Benazeprilat disposition and effect in dogs revisited with a pharmacokinetic/pharmacodynamic modeling approach. J Pharmacol Exp Ther. 2000 Mar;292(3):1087-93. Ref2. Gisleskog PO, Hermann D, Hammarlund-Udenaes M, Karlsson MO. A model for the turnover of dihydrotestosterone in the presence of the irreversible 5 alpha-reductase inhibitors GI198745 and finasteride. Clin Pharmacol Ther. 1998 Dec;64(6):636-47. Ref3. Bauer JA, Fung HL. Pharmacodynamic models of nitroglycerin-induced hemodynamic tolerance in experimental heart failure. Pharm Res. 1994 Jun;11(6):816-23. Regards, Joga Gobburu, Pharmacometrics, CDER, FDA