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It makes intuitive sense that improving bioavailability will reduce between-subject variability in
exposure.
Is anyone aware of a review which supports this view?
Charlie
KinetAssist Ltd
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Interesting question, not sure if there is a review talking about this. In a manuscript soon to be
submitted looking at switching between generic and brand lamotrigine products. Using replicate
testing we found greater variability within products than between products.
Timothy E Welty PharmD FCCP BCPS
Professor and Chair
Department of Clinical Sciences
College of Pharmacy and Health Sciences
Drake University
2507 University Avenue
Des Moines, IA 50311-4505
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Charlie,
I think what you might be looking for is discussed in the article "Interpatient variability in
bioavailability is related to the extent of absorption: Implications for bioavailability and
bioequivalence studies" by Hellriegel ET, Bjornsson TD, Hauck WW.
Thanks,
Brian Thompson
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Dear Charlie,
I am not sure whether such a paper would be available but I think it's mostly a fact-finding.
The "range of Fabs" (from the subjects) tends to 1 as you saturate the possible limits of absorption
(across the population) by making more drug available.
However if the intent to support this is for writing a manuscript or explaining to regulatory
agencies, I do not think a further fact-finding (literature) is required. This is simply maths.
Not only this fact applies for between subject but also for within subject variability too.
Regards,
Arindam Pal
Dr. Reddy's Labs. Ltd.
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Hi Charlie
Although I agree that a first impression is that the greater the bioavailability the less the
variability, on reflection I'm not sure that would be the case in published papers.
For example, if the mean is 5% there is not much room for differences in actual amount absorbed
compared with an 80% mean. In the first case a 4 or 6% result is only a 1% change of dose absorbed
despite being 20% away from the mean. When the mean is 80% it takes figures of 64 and 96%
absorption to reach the same percentage differences, which are relatively large amounts. Assuming
that the two medicines require similar total amounts to be absorbed for efficacy, the dose of the
first would be increased compared with the latter which would eliminate differences in assay results
and the lesser bioavailability would appear to be the more consistent. So, it seems that to meet
your expectation, it is necessary to assume that the higher bulk of the higher dose has itself
caused more variation, and I'm not sure that actually happens. However, there should be plenty of
published evidence that would include variance in means with dose, although I doubt that many
authors would make a point of it.
So, to reach your objective I think you are more likely to find evidence for or against your
expectation in publications that include data on mean bioavailability vs dose
Hope this helps
Andy
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Thanks to all who replied to this query.
The publication by Hellriedel et al, recommended by Brian, shows a clear inverse correlation between
absolute bioavailability and intersubject variability (for 100 drugs from 149 studies).
Charlie
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