Dear All,Back to the Top
Having the results of a two-compartment modelling of plasma data
obtained after oral administration in terms of Ka, V1, V2, CL and CLd,
we would like to quantify the respective AUC under the initial (alpha)
phase and the terminal (beta) phase.
For i.v. data, this can be easily obtained:
AUC(alpha)=A/alpha
AUC(beta)=B/beta
For extravascular data, is it possible to derive AUC(alpha) and
AUC(beta) directly from the parameters given here above, without having
to simulate the i.v. profile based on V1, V2, CL and CLd ?
Thank you in advance for your help,
Fabrice Nollevaux
www.sgsbiopharma.com
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Dear Fabrice,
You wrote:
"we would like to quantify the respective AUC under the initial (alpha)
phase and the terminal (beta) phase."
My question is: why do you want to quantify these 'partial' AUCs? In my
view, they do no mean anything. The discrimination between an initial
(alpha) phase and a terminal (beta) phase is purely arbitrary. Any
interpretation of 'distribution phase' and 'elimination phase' is also
purely arbitrary, since both distribution and elimination start at time
zero
and end at infinity. Of course I know that distribution is the
predominant
process during the 'inital phase' and elimination during the 'terminal
phase', but the change from 'predominant distribution' to 'predominant
elimination' is a gradual process, and, as far as I know, nobody has
ever
defined this exactly. So why bothering about it?
I can understand that there may be situations where the discrimination
between 'initial phase' and 'terminal phase' may be important, but one
has
to define the phases arbitrarily before anything can be calculated and
concluded.
"For i.v. data, this can be easily obtained:
AUC(alpha)=A/alpha
AUC(beta)=B/beta"
This calculation results in the AUCs under the two 'curve-stripping
lines'.
You may call this the AUC under the initial phase and terminal phase,
respectively, but I do not have a clear interpretation of these values.
Only
in case where the biexponential profile is due to a mixture of two
compounds
(e.g. a racemic mixture), each eliminated with a different clearance,
these
values have a clear interpretation. If I see the matter too simple,
please
let me know.
"For extravascular data, is it possible to derive AUC(alpha) and
AUC(beta) directly from the parameters given here above, without having
to simulate the i.v. profile based on V1, V2, CL and CLd ?"
I think that you can calculate AUC(alpha) and AUC(beta) as for the iv
data.
I am not sure whether to use the intercepts A and B from the
extravascular
fit, or to converts these intercepts to the intercepts referring to the
intravenous dose. Again, more important is the question: what do these
values mean? To what purpose you want to calculate them? Without a clear
answer to these questions, your original question cannot be answered.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-a-.farm.rug.nl
Dear Hans,Back to the Top
The purpose of calculating these areas is to establish the repeated
administration scheme for a Phase Ib trial based on these results that
were obtained after single administration at various dose levels during
the Phase Ia.
To achieve this, we want to know if the repeated dosing scheme should
be rather based on the alpha- or on the beta-half-life, depending on
the relative importance of each phase.
These two half-lives are very different with t1/2( beta) being 10 times
longer than t1/2(alpha). Moreover, CL/F and CLd/F being more or less of
the same magnitude, it is not clear from the compartemental results to
determine which is the dominant process between the disposition and the
elimination.
Probably that the both disposition and elimination processes should be
taken into account for our purpose, so we will rather have to simulate
different repeated administration scheme based on the single dose
results.
Thank you very much for your consideration,
Fabrice Nollevaux
SGS Biopharma, Wavre, Belgium
www.sgsbiopharma.com
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Dear Fabrice,
Thank you for your explanation. In the extreme cases of 'predominant
alpha-phase' or 'predominant beta-phase' your approach may work, but I
am
afraid it does not work in the situation between the extremes.
Did you consider to evaluate the dosing interval by simulating the
profiles
during steady state? Once you have the pharmacokinetic parameters,
either iv
or extravascular, you can easily calculate the concentration profile
during
steady state for any dosing interval. Even without any fitting or
modeling
the steady-state profile can be estimated using the superposition
principle.
In this manner you can make a reasonable choice for the dosing interval,
based on the predicted concentration profile. IMHO, this makes much more
sense than the AUC-alpha and AUC-beta approach.
Best regards,
Hans
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-a-.farm.rug.nl
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Dear Fabrice,
I would recommend using the Mean Residence Time (MRT) in these cases, as
this is basically a "half-life" which has already been appropriately
weighted by the various fractional AUCs under the different 'phases' of
the curve.
The issue often arises when a compound that presents 'highly
compartmentalized' kinetics after intravenous administration, is
measured with an assay where the LLOQ is near to one of the 'transition'
points' of the concentration curve. One then gets results for example,
where half the subjects (usually animals in my case) are t1/2 = 2 - 3
hr, while the remainder may be t1/2 = 8 -12 hr - simply because of the
number of measurable points used. In these cases, I suggest one avoid
dependence on half-life and use MRT instead, as MRT is not overly skewed
by a long "terminal phase" that is only reached at low concentrations,
and therefore represents a minimal fraction of the AUC of the drug.
I hope that this is helpful.
Peter J Rix
Drug Safety and Disposition
Ligand Pharmaceuticals, Inc.
San Diego, CA 92121
Email: PRix.-at-.ligand.com
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