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We are performing a PK/bioavailability study of IV and IM administration of a
muscle relaxant. Because the study is conducted in anesthetized children, it
is not a crossover design. The PK analysis supports the use of a
3-compartment model. However, the usual first order absorption model fails to
fit the data well -- in the IM group, late concentrations are consistently
higher than predicted, suggesting delayed absorption not accounted for with
this model. Lewis Sheiner suggested the following model:
Permit the absorbed dose to be partitioned into two absorption compartments
with different rate constants. The fraction of drug absorbed from each of
these compartments is then estimated in the analysis.
This model markedly improves the quality of fit of the model to the data
(i.e., the bias disappears). The resulting absorption halflives are 11 and 43
minutes with ~ 72% absorbed with the faster rate constant.
Our thought was that such a model might be a logical representation of drug
absorption from muscle -- some drug is deposited near the capillary and is
absorbed rapidly, other drug is further from capillary and is absorbed more
slowly.
A quick review of Medline fails to reveal that this issue has been addressed
previously. Does anyone have relevant experience or know of any published or
unpublished data that are relevant?
Dennis Fisher
Professor of Anesthesia and Pediatrics
University of California, San Francisco
fisher.-a-.zachary.ucsf.edu
[I've played with the same model after oral administration - thinking
possibly one is stomach the other is intestine ... or one may be insoluble
the other soluble ... I seem to remember that empirically similar models
can be developed with consecutive steps as well as zero order changing to
first order as in dissolution and absorption steps ... your thoughts re
close/far from capillary are reasonable but is solubility an issue? - db]
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[A few replies - db]
From: "Bruce CHARLES"
Organization: School of Pharmacy
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Date: Fri, 16 Oct 1998 10:18:12 +1000
MIME-Version: 1.0
Subject: Re: PharmPK Two compartment absorption model --- REPLY ---
X-Confirm-Reading-To: "Bruce CHARLES"
X-pmrqc: 1
Priority: normal
TO: Dennis Fisher
We have started to look at a generally similar situation with subcut. insulin
administration in young diabetic kids, using a population PK approach. A
delayed absorption also is evident with this drug, which has been (partly)
explained by delayed difussion across to the capiliaries.
The main problem with setting up sophisticated models (at least with our
insulin PK studies) is collecting enough data in patients to support them,
particularly with an apparent early, "non-linear" absorption phase.
Have a look at the following insulin papers which may be helpful if applied to
your situation:
Mosekilde, E., et al. Modeling absorption kinetics of subcutaneous injected
soluble insulin. J. Pharmacokinet. Biopharm. 17:67-87;1989.
DeMeijer, P., et al. A comparison of three mathematical models to describe the
disappearance curves of subcutaneously injected 125-I labelled insulin.
Br. J. Clin. Pharmac. 27:461-467:1989.
Cheers,
BC
Bruce CHARLES, PhD
Senior Lecturer
School of Pharmacy
The University of Queensland
Brisbane, QLD Australia 4072
TEL: +61 7 336 53194
FAX: +61 7 336 51688
Email: Bruce.aaa.pharmacy.uq.edu.au
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From: Maria Durisova
Subject: Re: PharmPK Two compartment absorption model
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Date: Fri, 16 Oct 1998 09:52:15 +0100 (MET)
MIME-Version: 1.0
Daer Professor Fisher,
In our study :
Durisova M., Dedik L., Balan M.: Building a structured model of a complex
pharmacokinetic system with time delays, Bull. Math. Biol., 57, 1995,
787-808,
we presented a new technique for modeling pharmacokinetic systems
containg time delays and we demostrated this technique using the example
of gentamicin bioavailability after intratracheal administration.
The technique allowed to determine the model,
to estimate four fractions of the drug obeying different
kinetics, and to estimate MRT of these fractions.
We used this modeling technique also in our recent study:
Dedik L., Durisova M., Srikusalanukul W., McCullagh, P.:
Structured model of lymphocyte migration under physiological
conditions,
presented at The Annual Meeting of the Czech and Slovak Pharmacological
Society, Prague, September 12-15, 1998.
Results of this study are available on the slides prepared
in PowerPoint 7.
Dr. Maria Durisova, PhD.,
Institute of Experimental Pharmacology
Slovak Academy of Sciences
SK-842 16 Bratislava
Phone/Fax: 00421375928
http://www.savba.sk
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From: honghui.zhou.-a-.pharma.Novartis.com
X-Lotus-FromDomain: PH.-a-.N1
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
Date: Fri, 16 Oct 1998 08:37:33 -0400
Subject: Re: PharmPK Two compartment absorption model
Mime-Version: 1.0
Dear Dennis:
We have some experience with the relevant models you mentioned. In one
food-interaction (meal timing) study, we found that the deconvolved
absorption profiles following oral administration under both fasted and fed
conditions could not be estimated well by usual first order absorption
model. The model incorporating with one fast absorption phase and one slow
one could significantly improve the model. The results will be presented in
this year's AAPS. You could find the abstract in AAPS Abstract Online. The
title is "Population Absorption Analysis: Effect of Meal Timing on the Oral
Absorption of SDZ HTF 919."
Additionally, similar concept has been utilized as well to successfully
model the population PK of IM Sustained-Release formulation (microsphere).
The PK profile was characterized by an initial peak followed by a typical
sustained-release profile. The results have been submitted to ASCPT 99.
Hope it is of any use to you.
Best regards,
Honghui Zhou, PhD
Clinical Pharmacokineticist
Dept. of Clinical Pharmacology
Novartis Pharmaceuticals Corp.
East Hanover, NJ 07936
honghui.zhou.-a-.pharma.novartis.com
(973)-781-2714 (o)
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X-Sender: hmehler.-a-.pop.mindspring.com
Mime-Version: 1.0
Date: Fri, 16 Oct 1998 16:50:41 -0700
To: PharmPK.at.pharm.cpb.uokhsc.edu
From: howard s mehler phd jd & assoc inc
Subject: Re: PharmPK Two compartment absorption model
Is the uptake of the muscle relaxant across the capillary wall
diffusion or receptor mediated? If receptor mediated you may want to
consider the possibility of the existence of two populations of receptors
with different binding and transport kinetics, ie high affinity receptor (
low Km) and low affinity receptor. It may be illustrative to measure blood
concentrations as a function of time over a range of IM doses to delineate
the two absorption compartments. . .
Regards,
Howard S Mehler
Howard S Mehler PhD JD & Assoc Inc
6399 Wilshire Blvd Suite 310
Los Angeles, CA 90048
hmehler.aaa.mehler.com
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