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Dear all,
Since I'm not a statistician or pharmacokineticist I would really
appreciate explanation of influences that could lead to a sequence
effect in 2 period, cross-over bioequivalence study?
Could you advise me any literature to further enlighten this problem?
Thank you in advance!
Tanja Čeligoj, DVM
Researcher
Lek Animal Health
Slovenia
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The sequence effect at ANOVA has the purpose to 'see' a real difference
between the groups whose subjects were randomised for the available
sequences.
For example: at a 2 way crossover study, with form A (Test) and B
(Ref.), one group is formed by subjects randomised for the sequence AB
and the 2nd group by subjects randomised for the sequence BA.
Although, three 'factors'€ť can confound a significant sequence effect:
1. a real difference between the two groups of subjects(for example at
the eliminating/metabolising rate, etc). This factor is minimized by
the good clinical selection of subjects;
2. a different carry over effect for the formulations. Once the
comparison is between the same type of formulations, i.e. immediate
release or prolonged release, for the same active moiety and type of
forms, the elimination rate should be the same (same average and CV for
the groups). Also, the carry over effect is observed by non zero
concentrations at 2nd period, before dosing (it is advisable at least
4-5 t1/2 between periods);
3. an interaction formulation-period, that is minimized by the
maintenance of the study conditions on 2nd period.
Try to look at:
Ormsby E., Statistical Methods in Bioequivalence in Generics and
Bioequivalence, Jackson A.J. CRC Press, Inc., 1994.
Zintzaras E., The existence of sequence effect in cross-over
Bioequivalence trials. Eur. J. Drug Metabolism and Pharmacokinetics,
vol. 25, 3/4, 241-244, 2000.
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The following message was posted to: PharmPK
Tanja,
If you don't leave adequate washout time between the two periods you
could get a sequence effect.
You need to washout both the drug and the PD effects that alter
Absorption, Distribution, Metabolism and Elimination.
For a drug that is a suicide inhibitor of an enzyme and is also
metabolized by that enzyme, then you need to wait for enzyme levels to
recover.
We recently performed a study in which it appeared that the absorption
of the compound appeared to be enhanced for the 2nd dose even after a
96 h washout in which all active drug and metabolites was 85% gone
after 48 h. The drug is thought to enhance gastric blood flow but this
is not its primary pharmacological effect.
Susan
Sr. Pharmacokineticist
Otsuka Maryland Res. Inst.
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)