Essar
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2006-02-28 12:40
(6422 d 16:06 ago)

Posting: # 77
Views: 11,603
 

 Phenotyping [Design Issues]

1. What is phenotyping?
2. What are its implications in certain BE Studies?

Regards,
Essar
Helmut
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2006-02-28 14:54
(6422 d 13:52 ago)

@ Essar
Posting: # 78
Views: 9,248
 

 Phenotyping

Dear Essar,

different Genotypes (coded in the individual Genome) express different forms (polymorphism) of proteins e.g., metabolizing liver enzymes (CYP450) and transporters (PGP). Individuals showing different forms are called Phenotypes.
For some drugs being metabolized we see different genotypes in the population (e.g., fast/extensive [aka EM] and slow/poor metabolizers [aka PM]).

In the general BE-setting this is of no interest, since the phenotype does not change (a poor metabolizer shows high concentrations both for test and reference, and a fast metabolizer low conc's...)

If your drug shows such a pattern (generally you notice it by a large inter-individual CV and ratio of >10 of the highest/lowest AUCs), two points are of interest:
If you plan a cross-over multiple dose study for such a drug, you may consider phenotyping in screening for safety reasons (i.e., include only FMs; otherwise you will end up in toxic range for the PMs). Example: paroxetine.
If you plan a parallel study, phenotyping is almost mandatory. Imagine a situation where you have by chance 5% slow metabolizers in one group, and 10% in the other; you results will be useless (the difference in concentrations will reflect the phenotypes, and not a difference in formulations). In such a case both groups should consist of an equal number of fast/slow metabolizers.

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Essar
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2006-03-01 09:24
(6421 d 19:23 ago)

@ Helmut
Posting: # 79
Views: 9,109
 

 Phenotyping

❝ If you plan a cross-over multiple dose study for such a drug, you may consider phenotyping in screening for safety reasons (i.e., include only FMs; otherwise you will end up in toxic range for the PMs). Example: paroxetine.


Dear Helmut,
Thanks for the clarification. Would need one more clarification:

Do we need to carry out Phenotyping for the single-dose, cross-over study also. We are planning to do the single-dose, cross-over BE study for Risperidone Tablets, and we have included phenotyping in this study. The justification provided by the concerned people is "to cancel out the inter-subject variability". But my question is that do we really require phenotyping in this study. Also, if inter-subject variability is a question, it will be taken care of by ANOVA. What do you suggest? Please enlighten.

Regards,
Essar
Helmut
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2006-03-01 13:15
(6421 d 15:32 ago)

@ Essar
Posting: # 80
Views: 9,338
 

 Phenotyping

Hi Essar!

OK, risperidone shows polymorphism, so probably you will see a wide range of plasma concentrations in your study. If you perform phenotyping, you will have an explanation for high (PM) and low concentrations (EM), but it does not...

❝ "cancel out the inter-subject variability"


You are exactly right that...

❝ inter-subject variability will be taken care of by ANOVA


So phenotyping is not necessary; it only gives you insights on the distribution of poor and extensive metabolizers in your study (which you don't need in BE assessment).

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