Susanh
☆    

Iceland,
2020-12-04 16:14
(324 d 15:50 ago)

Posting: # 22114
Views: 1,602
 

 partial AUCs for locally acting MR [Design Issues]

Dear all,

I’m involved in the development of a MR generic drug that is locally acting in the GI tract. Despite the very helpful new EMA guideline (Guideline on equivalence studies for the demonstration of therapeutic equivalence for locally applied, locally acting products in the gastrointestinal tract, CPMP/EWP/239/95 Rev. 1, Corr.1*) I´m struggling with designing the BE studies to support submission in EU.

Most problematic is the justification of the cut-off for the required partial AUCs.

Does anyone have suggestions how to approach this problem?

The modified release guideline (Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms EMA/CHMP/EWP/280/96 Rev1) suggests that the cut-off should be half the dosing interval but I fear that this may not be acceptable.

Thanks in advance,

Susan
jag009
★★★

NJ,
2020-12-05 08:01
(324 d 00:03 ago)

@ Susanh
Posting: # 22116
Views: 1,335
 

 partial AUCs for locally acting MR

Hi,

» I’m involved in the development of a MR generic drug that is locally acting in the GI tract. Despite the very helpful new EMA guideline (Guideline on equivalence studies for the demonstration of therapeutic equivalence for locally applied, locally acting products in the gastrointestinal tract, CPMP/EWP/239/95 Rev. 1, Corr.1*) I´m struggling with designing the BE studies to support submission in EU.
»
» Most problematic is the justification of the cut-off for the required partial AUCs.

Something like this in US for mesalamine ER?

https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_022301.pdf

J
Kumarnaidu2
☆    

India,
2021-05-28 11:55
(149 d 21:09 ago)

@ jag009
Posting: # 22375
Views: 664
 

 partial AUCs for locally acting MR

Hi all,

Recently we have conducted a pilot BE study of Mesalamine granules 4g. Partial AUCs (AUC0-12 and AUC12-t) were one of the primary parameters as this is for EMA. In this study AUC12-t parameter was not calculated as the concentrations after 12 were BLQ for almost all subjects except one or two subjects. what would be the possible reason for this?

Some solutions suggested by experts include
1) lowering the LLOQ range 2) Increase the dosage (but don't know the highest acceptable dose in healthy volunteer studies).

Any advice and suggestions will be a great help.

Thanks in advance

Kumar
dshah
★    

India/ United Kingdom,
2021-05-31 08:47
(147 d 00:17 ago)

@ Kumarnaidu2
Posting: # 22380
Views: 600
 

 partial AUCs for locally acting MR

Dear Kumar and Susanh!

Granulated mesalamine (5-aminosalicylic acid [5-ASA]), for maintenance of UC disease remission, is formulated for both delayed and extended release of mesalamine directly to the terminal ileum and colon.
As per few approved generics, partial AUC’s were also evaluated to match with reference as it was perceived to reflect drug absorption (and therefore drug availability) at the site of action in the colon.
In a first study, gastrointestinal transit was followed by gamma-scintigraphy after single-dose
application of tablets containing 1200 mg mesalazine to 12 healthy male volunteers.
In a study, gastrointestinal transit was followed by gamma-scintigraphy after single-dose application of tablets containing 1200 mg mesalazine to 12 healthy male volunteers. Tablet erosion started after 6.9 ± 1.1 h in the ascending or transverse colon. Radioactivity spread homogeneously throughout the colon, indicating the sustained release of active 5-ASA. Plasma kinetics indicated an earlier initial absorption of 5-ASA, i.e. during transit of the small intestine and ileum. Mean Cmax values (350.6 ± 322.6 ng ⁄ mL) were observed during location in the ileo-caecal region. The mean relative absorption of 5-ASA was 19.9 ± 18.2% in the small intestine and ileum and 80.1 ± 18.2% in the colon.

As per Lialda prescription information, Gamma-scintigraphy studies have shown that a single dose of 1.2 g (one tablet) passed intact through the upper gastrointestinal tract of fasted healthy volunteers. Scintigraphic images showed a trail of radio-labeled tracer in the colon, suggesting that mesalamine had distributed throughout this region of the gastrointestinal tract.

Dear Kumar, the observation for AUC12-t is strange as the Tmax is many times about 8 hrs and the half life is about 10 hrs.

I believe that AUC8-48 or AUC8-72 are required to prove that drug release is localized to colon.
Regards,
Dshah
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