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Hello,
Does anybody knows how to estimate multiple Taus (lag time) for oral
in ADAPT II? I tried to include several PO data (different dose
levels), and simutanouly estimate Taus for all doses, but it did not
work. It gave me error message "Only One Bolus Input allowed".
Is there any way to change Tau estimate subroutine? I appreciate your
help.
Thanks.
Alan
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The following message was posted to: PharmPK
Dear Alan,
Three options coming into my mind:
1) Population PK would be more powerful to analyze your data.
Alternatives with the STS-approach:
2) If you have single dose data with a sufficient washout period and
frequent sampling for each profile, split the data from each subject
and estimate a full set of PK parameters for each subject and study
period.
Between occasion variability (BOV) for clearance in healthy
volunteers after iv dosing tends to be small (often <15% CV) but may
be much larger in other situations (see Table 4 in
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/mss/tci/
tcibov.htm )
Coefficients of variation for the BOV in absorption half-life and lag-
time (Tlag) are often (>)>20%. Depending on your modeling objectives,
drug, and data you might have to consider BOV for both the absorption
and disposition parameters. You should consider BOV in extent of
absorption (F) which determines the BOV in CL/F and V/F after oral
doses. BOV in F can be substantial (>20% CV) for oral formulations.
3) If you cannot split profiles: Do not use the standard lag-time
statement in ADAPT at all, also not for the first dose. Instead,
create one absorption compartment for each dose and give a bolus dose
into each absorption compartment at the respective time of
administration, e.g. 0, 12, 24, and 36h. Then use one differential
equation for each of your doses and specify the absorption process
with IF THEN statements as follows (example for 4 doses):
a) from time zero to Tlag1 (inclusive): no absorption compartment
releases
b) from Tlag1 to (12h+Tlag2, inclusive): absorption comp. 1 starts to
release
c) from (12h+Tlag2) to (24h+Tlag3, inclusive): absorption comp. 2
starts to release
d) from (24h+Tlag3) to (36h+Tlag4, inclusive): absorption comp. 3
starts to release
e) after (36h+Tlag4): absorption comp. 4 starts to release (all
absorption comp. release now)
This way, you could apply the STS approach for rather "sparse" data.
I think that multiple bolus inputs work in ADAPT. If not, you could
use a 1 min (or 5min) infusion instead. That should cause only
negligible numerical differences in your results, if the step size of
the differential equation solver is short enough.
I have not yet used this type of code in ADAPT II, but have applied
such a code successfully in WinNonlin Pro as a user model compiled in
FORTRAN. I would not recommend to edit FORTRAN routines from ADAPT II
which are not expected to be changed by the user, unless you are sure
that this does not affect all the other ADAPT subroutines and
calculations.
Best regards
Juergen
--
Juergen Bulitta, MSc
Pharmacometrician, IBMP - Institute for Biomedical and Pharmaceutical
Research
Paul-Ehrlich-Str. 19, D-90562 Nurnberg-Heroldsberg, Germany
[I thought the model, error etc. subroutines were there for the user
to change in Adapt II with examples and help from the manual. Thus
the need for a fortran compiler. However, I have no real help for the
original question as I'm not sure of the problem. Are the differing
taus from multiple subjects or multiple doses? - db]
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