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I'm planning to investigate the absolute bioavailability of a drug for inhalation, administering the drug by inhalation and intravenously in a cross-over design.
In order to calculate the absolute BA, do I have to calculate the ratios of AUCih/AUCiv for each subject and then the mean value of F, or should I study the difference between the inhalation and the IV administration on the log-transformed AUC by analysis of variance?
In this bioavailability study, could it be of interest the statistical comparison (ANOVA) of CLr (renal clearance), fe (fraction of drug dose excreted with urine), CL/F (total clearance) e V/F (apparent volume of distribution) ?
Thank you very much in advance
Kind regards
Annalisa
--
Annalisa Piccinno
Clinical Pharmacologist
Corporate Clinical Development
Chiesi Farmaceutici S.p.A. Via Paradigna 63 43122 Parma (ITALY)
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The following message was posted to: PharmPK
Dear Annalisa,
You asked:
> In order to calculate the absolute BA, do I have to calculate the
>ratios of AUCih/AUCiv for each subject and then the mean value of F,
>or should I study the difference between the inhalation and the IV
>administration on the log-transformed AUC by analysis of variance?
I suggest to use the latter method, because it is the accepted method
used in bioequivalence studies, for several good reasons.
> In this bioavailability study, could it be of interest the
>statistical comparison (ANOVA) of CLr (renal clearance), fe (fraction
>of drug dose excreted with urine), CL/F (total clearance) e V/F
>(apparent volume of distribution) ?
CLr (renal clearance): CLr can be calculated from Ae/AUC where Ae is
the total amount excreted unchanged in the urine.
Using the AUC ratio for the calculation of F implies that you assume
that CL (total clearance) is the same on both occasions in the same
individual. Comparison of CLr allows for a check of the assumption; in
the case that fe is far below 1, this check is not really useful.
fe (fraction of drug dose excreted with urine): Usually fe is defined
as the fraction of the bioavailable dose excreted with urine. Not
really relevant if you calculated CLr.
CL/F (total clearance): CL is total clearance, assumed to be the same
on both occasions in the same individual. CL/F is a 'surrogate'
clearance used in cases where F is unknown. That is not the case here,
so I don't see any use of CL/F.
V/F (apparent volume of distribution): Estimation of V (not V/F, see
above for CL/F) can be done only using some modeling; in the most
simple case assuming a one-compartment model for the intravenous data.
For the inhalation data you need some modeling of the absorption
process as well, and you need the above mentioned assumption that
clearance is the same on both occasions in the same individual. If you
are really interested in V this could be done, but it is not relevant
from the bioavailability point of view.
best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics, Toxicology and Targeting
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
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