- On 25 Mar 2014 at 09:35:47, AnnaLog (trulala86.aaa.gmail.com) sent the message

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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! - On 25 Mar 2014 at 10:28:06, Wagner, Thomas (Thomas.Wagner.aaa.takeda.com) sent the message

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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 - On 25 Mar 2014 at 11:45:50, AnnaLog (trulala86.at.gmail.com) sent the message

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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. - On 25 Mar 2014 at 13:56:38, Nathan Teuscher (nathan.aaa.learnpkpd.com) sent the message

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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 - On 25 Mar 2014 at 15:43:13, Simon Davis (Simon.Davis.-a-.certara.com) sent the message

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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 ;-] - On 26 Mar 2014 at 09:04:14, David Bourne (david.-a-.BOOMER.ORG) sent the message

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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

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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 - On 18 May 2014 at 22:36:33, AnnaLog (trulala86.aaa.gmail.com) sent the message

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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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