Science vs. regulations [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2020-04-23 17:32  – Posting: # 21347
Views: 3,570

Hi qualityassurance,

that’s an interesting case.

» » Observed t½ (x±SD, range)?
» For reference (10.03 ±4.09, 3.5-19.0)
» For test (9.2 ±2.96, 3.22-17.0)
»
» » tmax, tlast?
» For reference: Tmax: 0.67, Tlast: 28.25
» For test: Tmax: 0.50, Tlast: 23.91

I played around with your data. Such an early tmax means that this IR product acts practically like a solution (absorption t½ 10–15 minutes). However, there is an extreme between-subject variability in elimination. That’s why you missed the 80% rule in some subjects.
In retrospect it would have been better to opt for truncated AUC0–72. Then you would not have to worry about extrapolation.
However, think about the subject line of the post. At 2×tmax absorption is practically complete (~96.12%). You could even take a very conservative approach with 4×tmax (~99.85%). We are interested in comparing the performance of the formulations, not to assess its well-known PK, right?
Hence, scientifically the large extrapolated AUC you see in some subjects is not relevant at all. Kamal Midha showed this nice example of partial AUCs. Once absorption is essentially complete, later T/R-ratios are extremely stable – only their variability increases.
If the assessor prefers to “tick-the-box-in-the-form”, cards are stacked against you. Sorry.

» Forgive me for the formatting. I tried my best.

No worries; I edited your post a bit.

Cheers,
Helmut Schütz
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