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Back to the forum  Query: 2017-08-23 23:09 UTC (UTC+2h)
 
javier
Junior

Spain,
2017-03-28 21:21

Posting: # 17196
Views: 954
 

 How to calculate this assumption...if AUCt is at least 80% of AUC∞... [Design Issues]

Dear All

First and foremost, I have been looking for a while in older post regarding this question, but although i have found some ideas, i dont have the main picture, so i kindly ask you to ilustrate all the beginners like me that we look here for enlightment

Regarding Bioequivalence studies on drugs with long half life, for example monoclonal antibodies or filgastrim,etc.... guidelines EMA and FDA says "AUCt will be ok if it is at least 80% of AUC∞."

the big question is how to calculate the amount of time to reach this conclussion about AUCt is at least 80% if you only have the information of the SmPC? (with so many important PK information omited ;-))

on another way: how to forecast the number of days that you will need to takes blood samples to cover the magic number of 80%?

in other post i have read that 2-4 times Tmax will be enought as a thumb rule, but if we are talking about intravenous infusion and long half life 's drugs i dont know if this rule will be applicable in this case or not

Thanks in advance for your time and if you ask me for the existence of this forum. I think a bebac book with all the information contained in the forum would be top list in amazon for a while..

Best regards

Javier
javier
Junior

Spain,
2017-03-30 11:36

@ javier
Posting: # 17212
Views: 789
 

 How to calculate this assumption...if AUCt is at least 80% of AUC∞...

If anyone knows a guideline or PK book when this issue es explained it would be very helpful too

thanks in advance
ElMaestro
Hero

Denmark,
2017-03-30 11:54

@ javier
Posting: # 17213
Views: 784
 

 How to calculate this assumption...if AUCt is at least 80% of AUC∞...

Hi javier,

» the big question is how to calculate the amount of time to reach this conclussion about AUCt is at least 80% if you only have the information of the SmPC? (with so many important PK information omited ;-))
»
» on another way: how to forecast the number of days that you will need to takes blood samples to cover the magic number of 80%?

This is not what you want to do. This what your boss wants you to do.
Biologics are much less defined that synthetic drugs, especially if they are produced by eukaryotic cells (S. cerevisiae etc). There are all sorts of little games going on with them which is not well understood and well controlled even in the most strictly regulated GMP facility. Check for example your batch release chromatograms (if you have them, if chromatolophystique is used where you work): You will see chromatograms that look like porcupines or someone having a really bad hair-day and where the individual spikes correspond to variants of post-translational modfication and where you don't really know
-exactly which ones are active
-their exact structure
-how potent they are
-and which ones aren't potent/active.

All these species may have different properties in terms of ADME. You will likely see differences in apparent t½ for Test and Ref.

I recommend that you do a pilot trial and forget all about the info on the SPC. You are facing a source of error that is potentially much much higher than what you are used to from synthetics.

I think a pilot trial in a dedicated phase I facility is also the ethically correct thing to do.

I could be wrong, but…


Best regards,
ElMaestro

- since June 2017 having an affair with the bootstrap.
javier
Junior

Spain,
2017-03-30 12:12

@ ElMaestro
Posting: # 17214
Views: 792
 

 How to calculate this assumption...if AUCt is at least 80% of AUC∞...

Hi ElMaestro!

» This is not what you want to do. This what your boss wants you to do.

I couldnt agree more with you :PCchaos:

» I recommend that you do a pilot trial and forget all about the info on the SPC. You are facing a source of error that is potentially much much higher than what you are used to from synthetics.
» I think a pilot trial in a dedicated phase I facility is also the ethically correct thing to do.

One more question,assuming that we will do the pilot trial, (in our case would be a healthy volunteer study because there is no safety concern about the drug)and the end of the day the question is the same right, How can we sure that que are taking enough sampling to cover the 80% of AUC-inf?

Forgive me for insisting but at heart i want to know how to do it just only for improving my kownlegde in pharmacology

Thanks in advance
ElMaestro
Hero

Denmark,
2017-03-30 13:08
(edited by ElMaestro on 2017-03-30 16:25)

@ javier
Posting: # 17215
Views: 773
 

 How to calculate this assumption...if AUCt is at least 80% of AUC∞...

Hola javier,

» One more question,assuming that we will do the pilot trial, (in our case would be a healthy volunteer study because there is no safety concern about the drug)and the end of the day the question is the same right, How can we sure that que are taking enough sampling to cover the 80% of AUC-inf?

The purpose of your pilot is dual: To get an idea of variability so that your can dimension your pivotal trial appropriately, and to establish the time by which AUCt>0.8*AUCinf in the majority of (expected future) trial patients/volunteers.

I could be wrong, but…


Best regards,
ElMaestro

- since June 2017 having an affair with the bootstrap.
javier
Junior

Spain,
2017-03-30 20:44

@ ElMaestro
Posting: # 17216
Views: 739
 

 How to calculate this assumption...if AUCt is at least 80% of AUC∞...

» The purpose of your pilot is dual: To get an idea of variability so that your can dimension your pivotal trial appropriately, and to establish the time by which AUCt>0.8*AUCinf in the majority of (expected future) trial patients/volunteers.

Thanks again for the answer (y por el tiempo que me has dedicado en contestar a la pregunta, que no es poca cosa) :-)

Best regards

Javier


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Helmut]
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