Bioequivalence and Bioavailability Forum

Tina
★

India,
2013-08-29 11:25
(4272 d 11:07 ago)

Posting: # 11376
Views: 10,265

Failed AUC 0-t [Study Assessment]

Dear all,

I have received the results of a pilot study of an IR product.
N=20

90% CI for Cmax is within the BE criteria. However, the upper value of the 90% CI for the AUC 0 to t is 135!. The ISV for AUC 0 to t is 24%.

My questions are:

If it were to be a product issue, would not both parameters be affected?
What are the causes for having only failing AUC 0-t?
Would increasing sample size (based on variability) to 28 be sufficient to counter the ISV of AUC 0-t?

Request guidance on the above study please.

Edit: Category changed. [Helmut]

Dr_Dan
★★

Germany,
2013-08-29 13:04
(4272 d 09:28 ago)

@ Tina
Posting: # 11377
Views: 8,942

Failed AUC 0-t

Post reply

Dear Tina
In order to give you advice I would need some further information:

What was the CVintra for Cmax?
I guess it is a drug with a very long elimination half live, right? Did you use truncated AUC?
If CVintra for Cmax << AUC and short t1/2, have you performed any outlier testing?
What was the point estimator (T/R ratio) for AUC? Maybe the formulation difference is too big to just calculate with CVintra and the usual delta 5%.


                            <<Sample Size Estimation>>                     

                                                                           

  Upper acceptance limit = 125 %

  Lower acceptance limit = 80 %

      Expected ratio T/R = 95.00 %

            Target power = 80.00 %

        Intra-subject CV = 24.0 %



crossover: n=26   

half replicated: n= 20   

full replicated: n= 14



         Estimated power = 80.76665 %

--------------------------------------------------------------------------



**Ref.:

 1. Hauschke D, Steinijans VW, Diletti E and Burke M. Sample size   

    determination for bioequivalence assessment using a multiplicative model.

    Journal of Pharmacokinetics and Biopharmaceutics. 20, 557-561 (1992).  

 2. Julious SA. Tutorial in biostatistics: Sample sizes for clinical trials 

    with normal data.  Statistics in Medicine. 23, 1921-1986 (2004).       

 3. Hauschke D, Steinijans VW and Pigeot I. Bioequivalence studies in drug

    development methods and applications. John Wiley & Sons, New York      

    (2007).

Kind regards
Dan

—
Kind regards and have a nice day
Dr_Dan

Tina
★

India,
2013-08-29 15:11
(4272 d 07:21 ago)

@ Dr_Dan
Posting: # 11378
Views: 9,139

Failed AUC 0-t

Post reply

Dear Dan,
Thank you for your reply.

Please find below the requested information:

❝ a. What was the CVintra for Cmax?

❝ b. I guess it is a drug with a very long elimination half live, right? Did you use truncated AUC?

Median t1/2: 20.2±16.19h. The product is an IR product and PK sampling was done till 72h.

❝ c. If CVintra for Cmax << AUC and short t1/2, have you performed any outlier testing?

I dont have information on this. Will update when I recive them.

❝ d. What was the point estimator (T/R ratio) for AUC? Maybe the formulation difference is too big to just calculate with CVintra and the usual delta 5%.

116 (T/R ratio) for AUC

Kind regards,
Tina

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! [Helmut]

Helmut
★★★

Vienna, Austria,
2013-08-29 16:33
(4272 d 05:59 ago)

@ Dr_Dan
Posting: # 11382
Views: 8,888

bear for replicates

Post reply

Hi Dan,

<nitpicking>

I would not use bear for sample size estimation of replicate designs. Like in FARTSSIE the 2×2×2 sample size n is estimated and the partial replicate’s calculated as ¾n or the full replicate’s as ½n – which is only approximately correct.
In the partial replicate you need a multiple of three subjects ≠ 20. ;-)

</nitpicking>

Therefore,
2×2×2: 26 (power 0.807666)
2×3×3: 21 (power 0.842808)
2×2×4: 14 (power 0.842482)

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Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Helmut
★★★

Vienna, Austria,
2013-08-29 15:58
(4272 d 06:34 ago)

@ Tina
Posting: # 11379
Views: 9,013

Failed AUC 0-t

Post reply

Hi Tina,

❝ 1. If it were to be a product issue, would not both parameters be affected?

Not necessarily.

❝ 2. What are the causes for having only failing AUC 0-t?

Likely better absorption. But a pilot study does not “fail” anyway.

❝ 3. Would increasing sample size (based on variability) to 28 be sufficient to counter the ISV of AUC 0-t?

No – unless you opt for a crazy sample size of 126 subjects (T/R 116%, CV 24%, 80% power). 126 is only applicable if you expect to exactly repeat the T/R and CV in a pivotal study – which is not a good idea. If you use the upper confidence limit of the CV (33.7%) you would need 240 subjects…

I would reformulate. BTW, what was the ratio for C_max?

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Tina ★ India, 2013-08-29 19:48 (4272 d 02:44 ago) @ Helmut Posting: # 11388 Views: 9,006	Failed AUC 0-t Post reply
	Dear Helmut, ❝ I would reformulate. BTW, what was the ratio for C_max? 116 was the ratio for C_max. Reformulation for an IR product is quite tricky esp if Cmax is matching. This scenario is possible for MR product for which IVIVC will give a clear picture. How would reformulation be planned for an IR product with matching Cmax but dissimilar AUC 0-t? Can IVIVC be done for IR product?

Helmut
★★★

Vienna, Austria,
2013-08-29 20:24
(4272 d 02:08 ago)

@ Tina
Posting: # 11390
Views: 8,883

Correct numbers?

Post reply

Hi Tina,

❝ ❝ I would reformulate. BTW, what was the ratio for C_max?

❝

❝ 116 was the ratio for C_max.

OK, identical to AUC. So the behavior is according to the textbook.

❝ Reformulation for an IR product is quite tricky esp if Cmax is matching. This scenario is possible for MR product for which IVIVC will give a clear picture.

❝

❝ How would reformulation be planned for an IR product with matching Cmax but dissimilar AUC 0-t?

You have the same ratio for AUC and C_max, both pointing in the same direction – higher absorption. I would not call a C_max-ratio of 116% “matching”. Actually I don’t understand your problem. You have a better formulation. Now make it as bad as the reference.

What you have given so far: n 20
AUC upper CL 135%, ratio 116%, CV 24%.
C_max passing BE (so upper CL ≤125%), ratio 116%, CV 25%.
Your numbers don’t makes sense. If I assume the worst case for C_max (upper CL 125%) in order to get a ratio of 116%, the lower CL would have to be ~108%* – which gives for n 20 a CV of 13.7% – not the 25% you stated.
I don’t like this question and answer game. In the future please give all required information already in the first post (ratio, CI, CV%, sample size for all relevant PK metrics).

❝ Can IVIVC be done for IR product?

No. Makes only sense if disintegration/liberation/dissolution is the rate-limiting step.

100×1.16²/1.25=107.648%

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

luvblooms
★★

India,
2013-08-30 11:23
(4271 d 11:09 ago)

@ Tina
Posting: # 11393
Views: 8,844

Failed AUC 0-t

Post reply

Dear Tina

As Helmut has already mentioned

❝ You have the same ratio for AUC and Cmax, both pointing in the same direction – higher absorption.

Now coming to your specific questions

❝ 1. If it were to be a product issue, would not both parameters be affected?

Yes, most likely it is a product issue. As 116% T/R ratios for Cmax and AUC clearly indicates that there is higher absorption.
How about looking into the formulation details too, for e.g. use of surfactant (Surfactants not only increase solubility but also increase permeability), particle size data (finer particles or so) etc, role and impact of used excipients on invivo performance.

You shall also look into the dissolution data as well, might not get IVIVC but some correlation can be obtained

I need to know few thing to help you in a better way

BCS class of the drug /pH solubility profile
whether the study was fasting or fed?
Tmax of the molecule

❝ 2. What are the causes for having only failing AUC 0-t?

May be higher Intra subject CV as with the same T/R ratio Cmax is comfortable.

❝ 3. Would increasing sample size (based on variability) to 28 be sufficient to counter the ISV of AUC 0-t?

Already answered by Helmut, You can go ahead if

❝ […] you opt for a crazy sample size of 126 subjects (T/R 116%, CV 24%, 80% power).

Edit: Standard quotes restored. [Helmut]

—
~A happy Soul~

Failed AUC 0-t [Study As­sess­ment]

Failed AUC 0-t

Failed AUC 0-t

bear for replicates

Failed AUC 0-t

Failed AUC 0-t

Correct numbers?

Failed AUC 0-t

Failed AUC 0-t [Study Assessment]