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The following message was posted to: PharmPK
Dear readers,
We had been conducting a dose escalation study of a drug in rats. The
drug was administered by iv bolus or PO. If we were to compare the
mean AUC's at each dose level, we would conclude that there was a
greater than proportional increase in AUC with increase in dose (over
the studied dosage range). If, on the other hand, we were to look at
the dose-normalized AUC's (AUC/dose), the opposite is seen: Far less
than proportional increase in AUC with increase in dose, and a
significant decrease in dose-normalized Cmax with increase in dose,
especially after the iv- route. Can we conclude that there was
dose-dependet kinetics present, and if so, shouldn't we observe just a
less than proportinal increase in Cmax with dose, rather than
decreasing Cmax with dose?
Should one compare the dose normalized values or just the actual values
for Cmax and AUC at each dose level?
Any suggestions would be greatly appreciated.
Natalie
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The following message was posted to: PharmPK
Dear Natalie,
Really your results are a bit strange. In order to help you is
important to
know which is the design of your experiment as well as information about
the actual doses and the variability of your results.
How have you calculated your parameters (non compartimental or
compartimental model)?
How have you calculated the mean AUC/D (actual doses for each rat or
theoretical doses)?
Best regards
Daniel Martínez
RIA Laboratory
Metabolism & Pharmacokinetics Service
Research & Development Department
IPSEN PHARMA, S.A.
Ctra. Laureŕ Miró 395
Sant Feliu de Llobregat, Barcelona, Spain
daniel.martinez.aaa.beaufour-ipsen.com
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The following message was posted to: PharmPK
Natalie:
The statistical comparisons should always be done on dose normalized
Cmax and AUC values (i.e. Cmax/D and AUC/D values) across the dosages.
Then only one can determine the dose-proportionality. Also, for a
single dose study AUC (0-inf) and multiple dose study AUC(0-t) are the
appropriate parameters for dose-proportionality comparisons. Hope this
helps.
- Chandra
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