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Dear all,
maybe someone can help me with this problem:
I need to analyze dose normalized AUC (dAUC) for two different formulations (Form. A molecular
weight: 100g/mol and formulation B (reference drug): 250g/mol) with 2 dosing steps. Molecular weight
of the actual drug is 150g/mol.
Dosing steps for formulation A: 390mg and 780mg + formulation B: 500mg and 1000mg.
Bioequivalence has already been proven. That’s why I calculated dose normalized AUC for both
formulations by dividing the AUC through Dose(Reference). But I am not sure if this is the right
approach.
For example: dose normalized AUC(Formulation A): AUC(Formulation A)/Dose(Formulation B)
Isn’t it better to adjust all dosing steps and formulations to eqimolar weight of the actual drug?
Here is one example how I calculated dose normalized AUC by normalizing to equimolar doses of the
drug:
780mg * 100g/mol= x *150g/mol
X= (780mg*100g/mol)/150g/mol
Dose normalized AUC= AUC/x
Performing LMEM (and bioequivalence testing) revealed a signficant difference between both
formulation (which is not possible) even if I split the analysis into the different dosing steps…
Can anyone tell me if this is the right approach?
Thanks in advance!
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I assume the formulation are different salt forms of your drug and I also assume you do not measure
salts in your PK assay. If so, you should use the molecular mass of actual drug and not of the
different salt derivatives
Best
Thomas
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Ah I am so sorry. I meant molecular mass... I wrote it very confussing.
Formulation 1 is a prodrug, MW: 250 Dose1: 500mg Dose2: 1000mg
Formulaton 2 is the salt of the active drug, MW: 150 Dose 1: 390mg, Dose2: 780mg
Dose 1 of formulation 1 is equivalent to dose 1 of formulation 2.
Dose 2 of formulation 1 is equivalent to dose 2 of formulation 2.
MW of active drug: 100.
Formulation 1 is the reference drug.
I have to analyze a 4x4 crossover interaction study. I tried to calculate the corresponding
equivalent dose of the active drug but something is wrong. When performing bioequivalence analysis
or LMEM it tells me both formulations are not equivalent or there is a signficant difference between
them respectively.
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Thanks for the clarification. This makes more sense.
I would convert the doses to common units. For example, Formulation 1 doses could be expressed as
390 mg eq and 780 mg eq for the 500 mg and 1000 mg doses of prodrug, respectively. Now everything
has the same dose "unit" and you can dose normalize by dividing the exposure parameters by the
appropriate dose. I would write the doses this way for your calculations.
Formulation 1:
Dose 1 = 390 mg eq active = 500 mg prodrug
Dose 2 = 780 mg eq active = 1000 mg prodrug
Formulation 2
Dose 1 = 390 mg active
Dose 2 = 780 mg active
Nathan
--
Nathan S. Teuscher, PhD
Founder and President, PK/PD Associates
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AnnaLog,
When you say " both formulations are not equivalent or there is a signficant difference between them
respectively." Which do you mean?
Note it IS possible for forms to be bioequivalent yet significantly different from each other.
If you are perfroming your analysis in Phoenix WinNonlin you could try posting the project to the
discussion forum www.pharsight.com/extranet so we can see your actual data and analysis steps and
advise better.
Simon.
[Or you could post some example data here (avoiding tabs if possible) - db ;-]
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Dear AnnaLog,
I agree with Thomas' analogy. Since the bioassay quantifies only the active, you need to divide the
AUC of each formulation by the Mwt of the active drug (i.e. 100mg) for AUC/D.
Best regards,
Magnus Atemnkeng
magnusajong.at.yahoo.com
--
Reply to Nathan:
This is what I also assumed.
Is it ok to calculate dose normalized AUC this way:
Dose 1 = 500mg eq active (formulation 2) = 390mg (formulation 1)
dose normalized AUC (formulation 2) = AUC/(dose of formulation 1)
If I do it this way I do not have any problems with further analysis.
My reference is formulation 1 (prodrug).
I am not sure if this is the right approach.
AnnaLog
--
Dear Simon,
I do have bioequivalence when looking at both formulations at each
dosing step using the acutal AUC. Using dose normalized AUC as
calculated aboth I also get the same results for each dosing step.
But I need to compare all dosing steps together for both formulation.
Trying to analyse the data with dose-normalized AUC mentioned above:
dose normalized AUC (formulation 2) = AUC/(dose of formulation 1)
I also have bioequivalence.
Trying to calcuate the corresponding dose of the active drug I do not
have bioequivalence. In my first post I showed the calculation steps.
What data do you need? Descriptives? Bioequivalence results?
Thanks in advance!
AnnaLog
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Dear all,
because I do not want to start a new topic I would like to ask you for help with another question
concerning dose normalized AUC/Cmax.
There are two different formulations and also different dosing steps (same drug as mentioned above)
I tried to calculate dose normalized PK parameters for the metabolites using equimalor doses of the
active drug. Also I tried to calculate AUC/Cmax by calculating equimolar doses in relation to the
molecular weight of the metabolites.
When splitting up in different dosing steps I receive totally different results in stat. analysis
for dosenormalized AUC/CMax than for not dosenormalized parameters. Is this possible? I would assume
results should be similar? Do I really have to calculate dose normalized PK parameters for
metabolites?
Hopefully someone can help me.
P.S.: If you know any literature on this subject please let me know.
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