Bioequivalence and Bioavailability Forum

Clarc
☆

Romania,
2013-11-19 12:04
(4190 d 06:25 ago)

Posting: # 11911
Views: 11,453

Failed Fed study on Indapamide MR [Study Assessment]

Dear all

We have just performed a 2x2x2 fed state study with 26 volunteers on indapamide MR. This generic has already passed the fasting study a few years ago. The dissolution tests are ok.
However in the fed study, the AUC passed, but the Cmax failed:

AUC:

Reference Confidence Interval:            [  0.8,      1.25   ]


Geomean Ratio (Test/Reference) = 0.930233

90% standard confidence interval

(around the ratio:[test form]/[ref form])=[  0.83186,  1.0402 ]


t(0.05 - 24df) = 1.7109

Cmax

Reference Confidence Interval:            [  0.8,      1.25   ]


Geomean Ratio (Test/Reference) = 0.680132

90% standard confidence interval

(around the ratio:[test form]/[ref form])=[  0.61796,  0.74855]


t(0.05 - 24df) = 1.7109

In your opinion this failure of Cmax is caused by the formulation, or is there something else with influence on our results?

Thanks

Edit: Category changed. [Helmut]

—
I'm always tryin' to do something new, tryin' to look like a beginner.
Meshell Ndegeocello

Dr_Dan
★★

Germany,
2013-11-19 15:31
(4190 d 02:58 ago)

@ Clarc
Posting: # 11913
Views: 10,380

Failed Fed study on Indapamide MR

Post reply

Dear Clark
A Geomean Ratio (Test/Reference) of 0.680132 and a 90% CI from 61.796 to 74.855 shows that this formulation will never get bioequivalent with the reference in the fed state. Test and reference formulation have a different food effect with regards to Cmax. This is nothing extraordinary. The intra-subject variability for Cmax of your study is 20% which gives a a posteriori power of the study of 90%. Therefore I guess the results of the study are not influenced by outlier but valid and you need to reformulate. :-(

I hope this helps.
Kind regards
Dan

—
Kind regards and have a nice day
Dr_Dan

ElMaestro
★★★

Denmark,
2013-11-19 16:56
(4190 d 01:33 ago)

@ Clarc
Posting: # 11915
Views: 10,274

Failed Fed study on Indapamide MR

Post reply

Hello Clarc,

I get a 26% CV for AUC, which is a bit higher than the observed CV for Cmax. Although this may happen, it is rarely the actual case and for that reason I raise an eyebrow. So I can't conclude anything, but I would investigate this if I were you; in particular I'd look at the raw data from the bioanalysis, esp. chromatograms.
In the past when I have triggered audits because of this phenomenon we have always been able to identify an 'issue' although in the grand scheme of things it has not been that many studies, and none of them were MR SODFs if I recall correctly.

—
Pass or fail!
ElMaestro

Helmut
★★★

Vienna, Austria,
2013-11-19 17:42
(4190 d 00:47 ago)

@ ElMaestro
Posting: # 11916
Views: 10,348

CV from CI

Post reply

Hi ElMaestro,

❝ I get a 26% CV for AUC, which is a bit higher than the observed CV for Cmax.

Which number-cruncher are you using? Mighty PowerTOST gives 23.9% for AUC and 20.4% for C_max. Try:

library(PowerTOST)

round(100*CVfromCI(lower=0.83186, upper=1.0402,  n=26, design="2x2"), 1)

round(100*CVfromCI(lower=0.61796, upper=0.74855, n=26, design="2x2"), 1)

—
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

ElMaestro ★★★ Denmark, 2013-11-19 17:59 (4190 d 00:30 ago) @ Helmut Posting: # 11917 Views: 10,264	CV from CI Post reply
	Hi Hötzi, ❝ ❝ I get a 26% CV for AUC, which is a bit higher than the observed CV for Cmax. You're right, I screwed up, 24% is more like it. Am using a OpenOffice Calc spreadsheet of my own making. Unfortunately it does not raise the alarm when the user types the wrong number... — Pass or fail! ElMaestro

Helmut ★★★ Vienna, Austria, 2013-11-19 18:05 (4190 d 00:24 ago) @ ElMaestro Posting: # 11918 Views: 10,327	Misprint gremlin Post reply
	Hi ElMaestro, ❝ Unfortunately it does not raise the alarm when the user types the wrong number... Like any other software. — 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

Clarc
☆

Romania,
2013-11-20 08:28
(4189 d 10:01 ago)

@ ElMaestro
Posting: # 11922
Views: 10,224

Failed Fed study on Indapamide MR

Post reply

Dear All

Thank You for the replies

Dear El Maestro

❝ So I can't conclude anything, but I would investigate this if I were you; in particular I'd look at the raw data from the bioanalysis, esp. chromatograms.

We have looked at the raw data, and the chromatograms too. Unfortunately the data tells me, that C_max for the test drug, is lower in 25 of 26 volunteers, and it's under 75% of the reference C_max, in about 20 volunteers.

To be more specific, and to complete the data: the AUC has made it, however the %AUCextra didn't.

Geomean Ratio (Test/Reference) = 1.38161

(around the ratio:[test form]/[ref form])=[1.1131,1.7149]

Clarc

—
I'm always tryin' to do something new, tryin' to look like a beginner.
Meshell Ndegeocello

jag009 ★★★ NJ, 2013-11-19 20:45 (4189 d 21:44 ago) @ Clarc Posting: # 11919 Views: 10,256	Failed Fed study on Indapamide MR Post reply
	Hi, ❝ We have just performed a 2x2x2 fed state study with 26 volunteers on indapamide MR. This generic has already passed the fasting study a few years ago. The dissolution tests are ok. ❝ However in the fed study, the AUC passed, but the Cmax failed: Can you tell us how successful you were in passing the fasting study? Wth flying colors or borderline? Thanks JOhn

Clarc ☆ Romania, 2013-11-20 08:36 (4189 d 09:53 ago) @ jag009 Posting: # 11923 Views: 10,187	Failed Fed study on Indapamide MR Post reply
	Dear John ❝ Can you tell us how successful you were in passing the fasting study? Wth flying colors or borderline? The fasting study has passed for `C_max with: 0.8918-1.0498, PE: 0.9676` and for `AUC_tot: 0.98166-1.1583, PE: 1.06633` Clarc — I'm always tryin' to do something new, tryin' to look like a beginner. Meshell Ndegeocello

luvblooms
★★

India,
2013-11-20 09:51
(4189 d 08:38 ago)

@ Clarc
Posting: # 11924
Views: 10,246

Failed Fed study on Indapamide MR

Post reply

Hey Clarc

A couple of questions first

a) what was the Tmax observed for fasting and fed study (for test and reference both)? Was there a wide differene?

b) Is there any plan to re-do the fasting study again?

b) From the data shared, one thing is obvious that your rate of release is slower in fed study as 25 of 26 volunteers and it's under 75% of the reference Cmax, in about 20 volunteers. But your extent remains ok, which tells that in later part your drug is coming out and getting absorbed. Does your formulation has any release controlling excipient which shows food effect? And What is the release mechanism (through erosion and/or diffusion or any other mechanism?)

c) Can you also let us know the time points used in the stduy? Since you AUC inf is higher ~138%, so there might be some issue related to the sampling time points (Kel not measured properly).

b) Was there any period effect? I know it is long shot but still it could give you some idea for AUC inf if there is a difference in Kel observed in different periods.

Edit: Is [a•b•b•c•b] a secret code? [Helmut] :-D

—
~A happy Soul~

Clarc
☆

Romania,
2013-11-20 11:59
(4189 d 06:30 ago)

@ luvblooms
Posting: # 11925
Views: 10,179

Failed Fed study on Indapamide MR

Post reply

Dear luvblooms

❝ a) what was the Tmax observed for fasting and fed study (for test and reference both)? Was there a wide differene?

In FED state:
T_max (mean) - Test: 9.8846 / Reference: 7.5385
In Fasting:
T_max (mean) - Test: 14.308 / Reference: 13.962

❝ b) Is there any plan to re-do the fasting study again?

As far as I know, the answer is NO.

❝ c) ... Does your formulation has any release controlling excipient which shows food effect? And What is the release mechanism (through erosion and/or diffusion or any other mechanism?)

Yes it has, HPMC. The release mechanism is mostly erosion, but diffusion is implied too.

❝ d) Can you also let us know the time points used in the stduy? Since you AUC inf is higher ~138%, so there might be some issue related to the sampling time points (Kel not measured properly).

Blood samples had been harvested:

pre-dose (0.0) and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 14.0, 16.0, 24.0, 36.0, 48.0, and 72.0 hours

❝ e) Was there any period effect? I know it is long shot but still it could give you some idea for AUC inf if there is a difference in Kel observed in different periods.

The calculated period effect for Cmax was: 0.717 (NS)

Clarc

—
I'm always tryin' to do something new, tryin' to look like a beginner.
Meshell Ndegeocello

jag009 ★★★ NJ, 2013-11-20 18:30 (4188 d 23:59 ago) @ Clarc Posting: # 11929 Views: 10,084	Failed Fed study on Indapamide MR Post reply
	Hi, Based on the information you have given us, I am afraid that reformulation is the way to go. John

luvblooms
★★

India,
2013-11-21 07:00
(4188 d 11:29 ago)

@ Clarc
Posting: # 11931
Views: 10,473

Failed Fed study on Indapamide MR

Post reply

Dear Clarc

❝ In FED state:

❝ T_max (mean) - Test: 9.8846 / Reference: 7.5385

❝ Yes it has, HPMC. The release mechanism is mostly erosion, but diffusion is implied too.

From the Tmax values in fed condition it looks like that the test formulation is having a stronger Matrix as compared to the reference.

In my experience, I have observed that higher viscosity grades of HPMC show a bit nasty behaviour in fed condition (slower release)as there will be lesser water for permatiion in formulation.

Thus most of the time we have used it in combination with lower viscosity grade HPMC or some other matix forming agents to maintain proper release.

And I agree to John on the reformulation option.

You can play with
a) different grade of HPMC (may be lower viscosity)
b) HPMC in combination with other excipients (PVP etc.)

❝ ❝ e) Was there any period effect? I know it is long shot but still it could give you some idea for AUC inf if there is a difference in Kel observed in different periods.

❝ The calculated period effect for Cmax was: 0.717 (NS)

Ok!! what about elemination pattern or Kel? Was there any differences observed in mean profile of each period.

While looking for the Indapamide MR, I came across one article which I think could be useful for you in further understanding (You must be having this one)

Galenic Development and Pharmacokinetic Profile of Indapamide Sustained Release 1.5mg; Clin Pharmacokinet 1999; 37 Suppl. 1: 13-19

Here they have played with percentages of MHPC and povidone, which permit a linear release in vitro of indapamide and later optimized the ratio of these 2 constituents to release of more than 70% of the dosage over 16 hours in a very reproducible manner.

Hope this would be of some use.

Regards

—
~A happy Soul~

Clarc ☆ Romania, 2013-11-21 08:11 (4188 d 10:18 ago) @ luvblooms Posting: # 11932 Views: 10,099	Failed Fed study on Indapamide MR Post reply
	Dear luvblooms, dear all Thank You for assisting me in this matter, and confirming my opinion on what we will have to do. Clarc — I'm always tryin' to do something new, tryin' to look like a beginner. Meshell Ndegeocello

Failed Fed study on Indapamide MR [Study As­sess­ment]

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