Bioequivalence and Bioavailability Forum • WinNonlin 2.1

valen
●

2006-06-15 14:19
(6518 d 09:32 ago)

Posting: # 149
Views: 8,048

WinNonlin 2.1 [Software]

Dear all,

I would be very grateful if anyone can help me in answering my questions:

1- in ANOVA section in winnonlin 2.1 there are three sub-sections "Contrast", "Tests" and "Least Squares Means" that I don't know what I have to put there. The Bioequivalence test runs without putting anything in there.can anybody tell me about the utility of these subsections?

2- when I run the bioequivalence test in 3x3x3 study with carryover effect
Seq + Subject(Seq) + Period + Trt + Carryovr

the program gives me the following error:

     Bioavailability Statistics



     Dependent variable: Cmax



     Alpha=0.0500  Bioequivalence Limits: (A.H.)Lower= 0.800 (A.H.)Upper= 1.200

     Transformation = NONE  Percent of Reference to Detect = 0.20

     Reference least squares mean not estimable



     Test : B             Least squares mean not estimable



     Test : C             Least squares mean not estimable

and when I eliminate the Carryover effect form the model it goes well.

Can any body help me in soving this problem?

Thank you very much in advance,

Helmut
★★★

Vienna, Austria,
2006-06-15 15:07
(6518 d 08:44 ago)

@ valen
Posting: # 150
Views: 6,116

WinNonlin 2.1

Post reply

Dear Valen!

Unfortunatelly I don't have access to v2.1 (the ANOVA module was replaced by the BE module [Linear Mixed Effects Modeling] in v3.2).

Maybe some remarks are helpful:

you should ln-transform your data, resulting in
Bioequivalence Limits: (A.H.)Lower= 0.800 (A.H.)Upper= 1.250
in a 3×3×3 design (as well as in a conventional 2×2) carry-over is confounded with other effects; therefore carry-over generally is not included in the model (lack of carry-over is verified by taking a plasma sample prior to administration in all periods, which should show concentrations <5% C_max).
for drawbacks of a 3×3×3 design have a look at this post and the followings.

The statistical test for carry-over^[1] is considered obsolete.^[2,3,4]

BTW, what data does your variable Carryovr contain?

References

JE Grizzle
The two-period changeover design and its use in clinical trials
Biometrics 21, 467-480 (1965)
PR Freeman
The Performance of the Two-Stage Analysis of Two-Treatment, Two-Period Crossover Trials
Statistics in Medicine 8, 1421-1432 (1989)
S Senn
Cross-over Trials in Clinical Research
2^nd Edition, Wiley, Chichester, pp 35-88/295-322 (2002)
Jones B and MG Kenward
The 2x2 cross-over trial. Consequences of preliminary testing, in:
Design and Analysis of Cross-Over Trials
2^nd Edition, Chapman & Hall, Boca Raton, pp 44-50 (2003)

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