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The following message was posted to: PharmPK
Dear All,
I have a question to the members regarding the period and sequence
effects, In one of our pilot studies we found both period and squence
effects
despite giving sufficient washouts and further there was no predose
concentration reported during the analysis. What could be the possible
reasons of these effects ?
Thanks
Manoj Kumar Vishwakarma
Group- Leader
Biopharmaceutics
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The following message was posted to: PharmPK
Hi Manoj,
You offer very little information for any assessment. What are these
effects that you mention and how you know that there is an effect? What
rout of administration do you use?
What comes to mind is enzyme induction/inhibition. Does your compound
induces or inhibits enzymes?
Toufigh Gordi
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The following message was posted to: PharmPK
Could you Please tell me what kind of ANOVA model you ran for seeing the
sequence effect. From the Overall model you can get period effect but
Sequence effect is always tested using subject nested within sequence as
the error term. Also these effect could be due to small sample size.
Hope it helps,
Shilpi Khan, M.S.
Staff Scientist/Biostatistician
CEDRA Corporation
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The following message was posted to: PharmPK
Hi all
Just a quick note. If you are modelling the data (e.g. using a PK or PD
type model rather than an ANOVA) then a sequence effect (carryover,
tolerance) would be part of the structural part of the model where as a
period effect is more likely to be a random effect indexed to the
subject
(perhaps interoccasion variability). Obviously without knowing the
details
then these are just guesses.
Steve
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Dear Manoj,
Assuming that the study is a crossover design with the same drug at the
same dose level adminstered orally (A typical BE study), the period
effect may be explained with the enzyme inhibition or induction.
In this case you may get altered plasma levels in the second period
despite giving sufficient washout time. This is especially true for
drugs which are extensively eliminated by first pass emetabolism. If
you compare the PK profiles of individual volunteer you may come to
some conclusions regarding period effect (may or may not be
statistically true value).
For statistical interpretation, please also consider the number of
subjects and the drug behaviour in vivo. For a highly variable drug,
the number of volunteers you have enrolled in your PILOT study may not
be sufficient to handle the period and sequence errors. Hope this
reference may help.
Tothfalusi etal, Evaluation of the Bioequivalence of Highly-Variable
Drugs and Drug Products Pharmaceutical Research, Vol. 18, No. 6, 2001.
Regards
Varma Manthena
Biopharmaceutics & Pharmacokinetics
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The following message was posted to: PharmPK
Dear Manoj:
You are wondering how come your pre-dose
concentrations are BQL but you see period effect. This
happens all the time. Some of our colleagues mentioned
enzyme induction/inhibition but in general biochemical
and/or physiological processes responsible for drug
disposition (mainly clearance and elimination) have
not yet recovered. This could be due to
induction/inhibition, saturation and/or toxicity. If
you every worked with liposomeal product you encounter
these types of observation which in most cases has
nothing to due with enzyme induction/inhibition.
Rostam
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The following message was posted to: PharmPK
Dear Manoj
Not possible to comment without having a look at data grid.
in a crossover PK study these effect may be of statistical significance
but not otherwise provided predose concentrations are zero, at least 10
half lives washout has been observed
regards
Dr.Prashant
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