Hello everyone!
I was calculating CVWR (in replicate designs) of different compounds in Phoenix WinNonlin using method described in section "3.5 Calculation of CVWR and Scaled Acceptance Range" in these instructions (starting on page 6):
https://bebac.at/dow...hoenix_v3.4.pdf
When I am calculating within reference CV (CVWR) for full-replicate 4-period design with 2 sequences (S1: ABAB, S2: BABA) everything looks fine and I get same CVWR regardless of the input order in Model specification Fixed effect (e.g. no difference when the input is "Sequence+subject+period", "period+subject+Sequence" ...) in Linear Mixed Effects (LME).
But when I am calculating CVWR for (semi- or full-?)replicate 3-period design with 2 sequences (S1:ABB, S2:BAA) I get 2 different CVWR. The CVWR I get depends on the input order in Model specification Fixed effect in Linear Mixed Effects (LME). This happened in 2 occasions (same design but 2 different studies and compounds):
A) For example, for compound X I get CVWR= 33,58% for three input orders "sequence+period+Subject", "period+Subject+sequence" and "period+sequence+Subject". On the other hand, for compound X I get CVWR= 33,91% for other three remaining input orders: "sequence+Subject+period", "Subject+period+sequence" and "Subject+sequence+period".
B)Similarly for the same design (ABB, BAA) but different study, for compound Y I get CVWR= 34,82% for same three input orders as mentioned above for compound X ("sequence+period+Subject", "period+Subject+sequence" and "period+sequence+Subject") and CVWR= 35,18% for same other three remaining input orders ("sequence+Subject+period", "Subject+period+sequence" and "Subject+sequence+period").
So my question would be, why is this so and which input order should be used in LME and gives the correct CVWR?
Additional question (just to check if this is the correct procedure) would be, if a subject 36 (sequence ABB) has a missing period 2 but returned for period 3 - like this:
Subject period sequence AUCi AUCt Cmax
36 2 ABB
36 3 ABB 495.60 479.6 48.5
We probably have to exclude whole subject 36 (both periods 2 and 3) when calculating CVWR? Because we get 2 different CVWR depending whether subject 36 is included (as above) or not?
Thank you and best regards
BEQool