[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 mononuclear cells). =
I observe a high accumulation in cells, but with a delayed absorption. I'm =
trying to fit the intracellular data dependent of the plasma pharmacokineti=
cs. The volume of distribution of the cellular compartment can be =
considered negligeble compared to the volume of distribution in plasma (no =
distribution to a second compartment can be observed in the plasma =
pharmacokinetics. However, cellular accumulation 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 have 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 and k32 was estimated =
to be very large, giving the same fit as estimating an accumulation ratio, =
which is not a good fit, since a delayed absorption in the cellular =
compartment was observed. There is some mass transport going on between =
the central and cellular compartments, that I do not want. My cellular =
pharmacokinetics depend on the plasmapharmacokinetics, but I don't want my =
cellular pharmacokinetics to influence my plasma pharmacokinetics, since =
this effect is likely negligible. Does 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_at_slz.nl
T: +31-20-5124737

Received on Tue Dec 09 2008 - 08:27:32 EST