partial AUCs for locally acting MR [Design Issues]

posted by dshah – India, 2021-05-31 08:47 (56 d 16:48 ago) – Posting: # 22380
Views: 299

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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