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I have designed a study for evaluating intersubject variability. I had
many doubts while designing the study which I mentioned below, please
provide answer to my questions. If any one knows any books or
reference give the same.
PLANNED STUDY DESIGN:
Objective: To evaluate the intersubject variability in healthy subjects
Study Design: Single dose, Single Period
Number of Subjects (Healthy): 30
Blood sampling: 0, 0.33, 0.67, 1.00, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0,
8.0, 10.0, and 12.0.
Estimation: Validated LCMS-MS method.
Pharmacokinetic calculation by using software like Winnonlin / SAS.
Evaluation of by comparing the large variation in serum drug levels
based on pharmacokinetic values (i.e. a coefficient of variation of
60% or greater)
1. Is this study design will be able to evaluate intersubject
2. Is the number of Subjects is sufficient to evaluate
3. Is single dose is sufficient to study intersubject variability?
4. Is single period is sufficient to evaluate intersubject
5. Is pharmacokinetic values comparison which I mentioned above
able to evaluate intersubject variability?
6. What are all the pharmacokinetic parameter should be taken in
to consideration? (i.e. Cmax, Tmax, AUC, Half life, Vd etc.)
7. Is the coefficient of variation of 60% or greater should be
checked for all the pharmacokinetic parameter or selected parameters
like Cmax, Tmax, AUC, Half life?
Please provide, if any other suggestion to carry out the evaluation of
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Why do you want to estimate inter-subject variability? Do you know
what you will do with the number when you get it? If you cannot give a
very clear answer these questions then you need to think of your
problem in a different way.
WinNonLin and SAS are not suitable tools for evaluating intersubject
variability. You should be thinking about non-linear mixed effect
programs that understand PK e.g. Monolix or NONMEM.
SAS has the a non-linear mixed effect procedure but it is very limited
in its abilities to deal with complex problems. Monolix and NONMEM are
a much better choice.
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
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