Restrictions on Subjects Movement during BE [Design Issues]
Just a few desultory thoughts...
❝ During the BE study, while lying in bed or in supine position is Not allowed after drug intake for at least 2 hours, can the volunteer subjects be allowed to stay standing, sitting or walking i.e. limited activity around the room where they stay after dose?
I remember one of Paula Muñiz Piniella’s lectures (hopefully correctly):
Two studies on a modified release formulation (gastric resistant); both demonstrated bioequivalence in the fed state, but:
- Study 1: CV was 20% for AUC, and 25% for Cmax, and
- Study 2: CV was about 11% for both metrics.
Since designs of both studies were essentially the same, let's look at the difference:
in the first study—in a large CRO—the administration was in standing position followed by 20 minutes sitting, then 1 hour lying on the right side, then 3 hours lying, whereas
in the second study—in a small CRO—administration was in standing position followed by sitting until 4 hours post dose.
One can only speculate that the over-restriction in the first study introduced variability: although under close observation, at least subjects may have moved only in one study period (lying on the right side for 1 hours is very uncomfortably) thus increasing the CV…
Moral of the story: the bigger is not always the better
❝ I understand that posture and physical activity of the subjects must be standardized, meals and fluid intake as well, during the study as the bioavailability of an active moiety from a dosage form could be dependent upon GI transit times, posture and physical activity.
Full ACK, but over-standardisation may lead to an ‘own goal’ (see above).
Of course sporting activities should be avoided (no ping-pong and tabletop football in the ward), but also exciting movies (whatever that means, maybe ‘Rambo I-III’ for males, and ‘Love Story’ for females)…
In my experience the atmosphere in mixed-sex studies is much more less tense than in ‘males-only’ ones
Don’t forget to standardise nutrition (subjects don’t like it, but it is a necessity to serve the same meals in all treatment periods); it may be an option to individualise the amount of meals for males/females.
Another point is food interaction, e.g., broccoli and grilled meat induces CYP1A2, whereas grapefruit juice inhibits CYP3A4; meals with a high content of proteins may increase liver blood flow, thus decreasing hepatic extraction of IR high clearance drugs…
Since up to 50% of the population show headaches upon caffeine withdrawal, you also may consider allowing some coffee—let’s say 4 hours post dose, if your drug is not metabolized by CYP1A2…
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
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