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RE: Modelling intracellular and plasma data

From: Troy, Steven <stroy>
Date: Tue, 9 Dec 2008 09:50:34 -0500

Dear Rob,

I am not an expert on intracellular PK models, but you=
r data appear to
be similar to a typical effect compartment PK system wit=
h a delayed time
to Cmax in the effect compartment relative to the time =
of Cmax in the
plasma compartment. If the PK in the intracellular comp=
artment does not
influence the PK in the plasma compartment (as you state=
d below), then
you cannot estimate both k23 and k32 independently. I =
suggest trying
the following modifications.

k32=theta(4); similar to Keo in an effect compartment mo=
del
k23=k32*v3/v1


Good luck!

Steve

Steven M. Troy
Senior Director
Global Clinical Pharmacology and Pharmacokinetics
Shire Pharmaceuticals
725 Chesterbrook Boulevard
Wayne, PA 19087-5637
 
Office: 1.484.595.8780
Mobile: 1.484.375.3692
Email: stroy

-----Original Message-----
From: owner-nmusers
m]
On Behalf Of Rob ter Heine
Sent: Tuesday, December 09, 2008 8:28 AM
To: nmusers
Subject: [NMusers] Modelling intracellular and plasma data

Dear all,

I'm trying to fit concentrations of a drug simultaneously =
measured in
plasma as well as intracellularly (in peripheral blood mon=
onuclear
cells). I observe a high accumulation in cells, but with=
 a delayed
absorption. I'm trying to fit the intracellular data depen=
dent of the
plasma pharmacokinetics. The volume of distribution of the =
cellular
compartment can be considered negligeble compared to the v=
olume of
distribution in plasma (no distribution to a second compar=
tment can be
observed in the plasma pharmacokinetics. However, cellular a=
ccumulation
depends on plasma concentrations.

I'm fitting the data with a first order oral absorption =
and elimination,
basically it can be summarized as:

$Model (DOSE) (CENTRAL) (CELL)

I have a rich sampling dataset of 11 individuals with =
at each timepoint
an observation in the cellular and plasma compartment. I =
have tried
several approaches for modelling cellular accumulation. I ha=
ve tried
fixing the cellular volume to a very small volume.

$PK
k12=theta(1)
v1=theta(2)
cl=theta(3)
k20=cl/v1
v3=0.0001
k23=theta(4)
k32=theta(5)

This didn't work. K23 was estimated to be very small a=
nd k32 was
estimated to be very large, giving the same fit as est=
imating an
accumulation ratio, which is not a good fit, since a d=
elayed absorption
in the cellular compartment was observed. There is some =
mass transport
going on between the central and cellular compartments, th=
at I do not
want. My cellular pharmacokinetics depend on the plasmapharm=
acokinetics,
but I don't want my cellular pharmacokinetics to influence=
 my plasma
pharmacokinetics, since this effect is likely negligible. Do=
es anyone
have a smart idea on how to code this?

Sincerely,

Rob ter Heine


_______________________________
Rob ter Heine, MSc, PharmD
Department of Pharmacology, Slotervaart Hospital
Amsterdam, The Netherlands
E: rob.terheine
T: +31-20-5124737


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Received on Tue Dec 09 2008 - 09:50:34 EST

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