Cl/F and V/F

From:Paul Hutson Subject:[NMusers] Cl/F and V/F Date:Mon, 29 Jul 2002 16:01:24 -0500 Greetings all: Using ADVAN2 TRANS2, I am fitting data from a parallel animal bioavailability study to determine the relative oral bioavailability of 5 new formulations, with the bioavailability of the initial product set to 1. In fitting the clearance (CL) and volume (V) to this 1 compartment model, I obtain a convergence and intra-subject variability in these parameters using the POSTHOC option. My understanding was that the CL and V values reported out by NONMEM for the i-th animal are in fact CL(i)/F1(i) and V(i)/F1(i). Therefore, by multiplying the output by F1, I anticipated that I would correct for the differences in relative bioavailability between formulations, eg: TVF1=1 IF(FORM.EQ.1)TVF1=THETA(1) IF(FORM.EQ.2)TVF1=THETA(2) IF(FORM.EQ.3)TVF1=THETA(3) IF(FORM.EQ.4)TVF1=THETA(4) IF(FORM.EQ.5)TVF1=THETA(5) F1=TVF1 KA=THETA(6); FIXED DUE TO LIMITED ABSORPTION PHASE DATA CL=THETA(7)*EXP(ETA(1)) V=THETA(8) CLT=CL*F1; CLT is true clearance SC=V/1000 VT=SC*F1; VT is true dist volume. Instead, the graph of the resulting CLT and VT show dichotomous values, varying by formulation. In contrast, the values of CL and SC reported out by the NONMEM fit are uniform over the different animals and formulations, with the intersubject errors of course adding some fuzziness. So, my question is, does NONMEM report out in ADVAN2 TRANS2 the "true" clearance and distribution volume, or are the values of CL and SC in fact CLtrue/F1 and Vtrue/F1? If the latter, why would my results for the CL*F1 and SC*F1 have such formulation-dependent breaks or separation of the means? Thanks, Paul (Leonid and Nick: Thanks for your previous comments. I am back on the listserve because of the general nature of this question.) Paul Hutson, Pharm.D. Associate Professor (CHS) UW School of Pharmacy 777 Highland Avenue Madison, WI 53705-2222 Tel: (608) 263-2496 FAX: (608) 265-5421 Pager: (608) 265-7000, #7856