PK and PD variability

Dear group, I am currently analyzing some dose-response data for one of our drugs. A simple Emax model nicely described the dose-response relationship for the principal PD variable (a continuous measure). Unfortunately, no PK data was obtained from the subjects in the PD study. Since the variability in the PD measure was quite high (CV>80% placebo, CV>100% active treatment) and variability in the AUC from previous PK studies was also high (55%, mainly due to variable bioavailability), the question is if reducing the variability in F (better formulation) would also relevantly improve PD variability. I have tried the following: - Adding an ETA to dose in the Emax model with IIV fixed to 55%CV (IIV_ED50 reduced from 100% to 75%) - Use the resulting estimates (including IIV_ED50, IIV_Placebo, residual variability,[Emax was fixed]) to simulate the response for different values of IIV_dose - Calculate the overall variability of the response (Note, that residual variability was also pretty high (approx 100%CV)) The results suggested that the overall PD variability would only decrease very little by reducing variability in F. However, I am unsure if my approach is acceptable and would like to have some input from the group. Thanks in advance, Andreas. Andreas Lindauer Pharmacokineticist Pharmacokinetics and Metabolism R&D Center. Ferrer Internacional S.A. Juan de Sada 32, 08028 Barcelona Tel +34 93 509 3265 Fax +34 93 411 2764 [email protected] www.ferrergrupo.com ¿Necesita imprimir este mensaje? Protejamos el medio ambiente. Li cal imprimir aquest missatge? Protegim el medi ambient. Do you need to print this message? Let's protect the environment. Este mensaje, y en su caso, cualquier fichero anexo al mismo, puede contener información confidencial, siendo para uso exclusivo del destinatario, quedando prohibida su divulgación, copia o distribución a terceros sin la autorización expresa del remitente. Si Vd. ha recibido este mensaje erróneamente, se ruega lo notifique al remitente y proceda a su borrado. Gracias por su colaboración. This message and its annexed files may contain confidential information which is exclusively for the use of the addressee. It is strictly forbidden to distribute copies to third parties without the explicit permission of the sender. If you receive this message by mistake, please notify it to the sender and make sure to delete it. Thank you for your kind cooperation. <<image/gif>> <<image/gif>>