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Improved absorption profile by forcing volume of the central compartment

From: B.C.M. Winter - De <b.dewinter>
Date: Tue, 24 Apr 2007 14:35:46 +0200

Dear NM-users,

Currently I am working on the PK data of a drug that is taken twice
daily orally. I have full AUC data from 45 individuals with 10 samples
per individual over a 12-hour period and abbreviated AUC data from 99
individuals with 5 samples per individual over a 2-hour period.
Individual plots and literature demonstrate that a 2-compartment PK
model with first order absorption and elimination and with a lagtime
should adequately describe the data. To model the data I used ADVAN4
TRANS4 with FO and a combined error model.

Problems occur with fitting the absorption phase of the drug, which
results in a structural underestimation of the peak concentration. Plots
of predicted versus observed concentration showed deviations from the
line of unity. Application of transit-compartments (Erlang) and more
flexible absorption profiles (eg Weibull) did not solve this problem.
However the fit could be improved by forcing the volume of the central
compartment to higher values, which resulted in higher Ka values, higher
peak concentrations, better individual plots in Xpose, but an increase
of the objective function.

What could be the possible reasons for these observations? Is it
appropriate to fix the distribution volume to higher values which
produce better goodness-of-fit plots but higher minimum objective
function values?
Thanks in advance for your time.

Brenda de Winter

/B.C.M. de Winter
Erasmus Medical Center
Department Hospital Pharmacy
Unit Clinical Pharmacology
Room L-056
's-Gravendijkwal 230
3015CE Rotterdam
the Netherlands

T +31 (0)10 46 33202
F +31 (0)10 43 66605

Received on Tue Apr 24 2007 - 08:35:46 EDT

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