Getting rid of correlation issues between CL and volume parameters

Dear all, I have come across an interesting proposal to account for correlation between CL and volume parameters by dividing by bioavailability within the NONMEM control stream: http://www.wright-dose.com/tip2.php I liked the approach, however I have been wondering how exactly to interpret the resulting parameter values for CL and V. As an illustration, a potential problem might be that we have doses of 10, 25 and 50 mg with a fixed bioavailability of 100% for the 10 mg dose, and bioavailabilities of 80% and 50% for the doses of 25 and 50 mg, respectively. In addition, a between-subject variability on F1 of ~30% would be present. If I now code my CL and V as follows: CL=THETA(1)/F1 V=THETA(2)/F1, to account for the correlation between CL and V, what exactly would be the meaning/interpretation of THETA(1) and THETA(2)? As the THETAs would be the same for all doses, the CL of 50 mg would be twice as high as the one for the 10 mg dose – does that make sense, as we already estimated the reduced relative bioavailability using parameter F1? Any comments would be very much appreciated. Thanks and best Nele Dr. Nele Müller-Plock, CAPM Principal Scientist Modeling and Simulation Pharmacometrics Experimental Medicine Takeda Pharmaceuticals International GmbH 8152 Glattpark-Opfikon (Zürich) Switzerland Visitor address: Alpenstrasse 3 8152 Glattpark-Opfikon (Zürich) Switzerland Phone: (+41) 44 / 55 51 404 Mobile: (+41) 79 / 654 33 99 mailto: [email protected] http://www.takeda.com -------------------------------------------------------------------- The content of this email and of any files transmitted may contain confidential, proprietary or legally privileged information and is intended solely for the use of the person/s or entity/ies to whom it is addressed. If you have received this email in error you have no permission whatsoever to use, copy, disclose or forward all or any of its contents. Please immediately notify the sender and thereafter delete this email and any attachments.