Re: mid-infusion higher than end of infusion
Peter, you do not specify what model you use. With any linear model in
PREDPP, or with the usual linear models in $DES, the drug in the depot
is governed by differential equations equivalent to
DADT(1)=R1-K10*A(1) ;where R1 is the infusion rate, K10 is elimination
This produces a monotonically rising A(1) which, if the infusion time is
great enough, reaches its steady state value DADT(1)=0, A(1)=R1/K10.
Sounds like this is what you expect to see.
But what if DADT is not linear? What if K10 increases with time, or
increases with rising A(1)? If for some reason the effective K10
increases with time, then A(1) will peak and then start dropping, even
as the constant rate infusion continues.
Or, F1 may in effect change with time. That is, effective R1 may
decrease with time, even though the infusion is constant.
Again, A(1) decreases from its peak.
Paul's suggestion that the drug is binding to something may well be
modelled as a change in F1 or effective K10.
If your drug goes into a depot and then to central compartment, then the
same remarks apply:
DADT(2)=K12*A(1)-K20*A(2)
may not apply. Maybe K20 increases with time, or increases with larger
A(2). Or maybe K12 falls with time, or falls with increasing A(2) or
decreasing A(1).
My suggestion is that you consider a non-linear differential equation,
using one of these ideas. You are all more familar with emax and
tolerance models than I am, so I will not say anything about the exact
form of such a model, or what the physiological explanation might be.
(Probably you know all this already, and it is only the physiology that
is in question.)
Quoted reply history
On Tue, 10 Jul 2007 14:11:26 -0500, "Paul Hutson"
<[EMAIL PROTECTED]> said:
> Peter: The low hanging fruit answer might be that your drug is binding
> to neutrophils, and that over the course of the infusion there is
> enhanced margination of these PMNs. Marginated to the endothelium,
> they and their adsorbed drug would not be measured.
> PS. Your book is great. Paul Bonate, Peter wrote:
>
> Dear all,
>
>
>
> I have a very unusual situation and wanted to see about getting the
> collective opinion on the group regarding the best way to handle this
> modeling problem. I have a drug that is given by 30 minute infusion.
> Samples were collected at predose, mid-infusion, end of infusion, and
> serial thereafter for 8 halflives. In about a third of the samples
> the mid-infusion sample had a considerably higher concentration (25 to
> 50%)than the end of infusion concentration. This phenomenon occurred
> across multiple studies, on multiple days (although not always in the
> same subject twice), and across multiple analytical runs. I have
> ruled out switched tubes and analytical error. For a variety of
> reasons this appears to be a valid phenomenon.
>
>
>
> Now, how best to model it or even explain it. The best I have been
> able to come up with is it is a distribution phenomenon. In
> discussions with another modeler I was informed that he just
> reviewed a paper having the same phenomenon and in that paper the
> authors discarded the midinfusion data. I have tried using time-
> dependent volumes using continuous and change-point functions. I
> get modest improvements in goodness of fit compared to completely
> ignoring the phenomenon which has a residual variability of about
> 30% using a 3-C model.
>
>
>
> As a company we have decided to pursue an oral formulation of this
> drug so it seems to me that modeling the iv data to the point of
> completely capturing the phenomenon may be a modeling exercise and not
> of any real value any longer.
>
>
>
> Any opinions on the validity of throwing out the data, just running
> with the model that ignores the phenomenon and has high residual
> variability, or something else I haven't been able to think of would
> be appreciated.
>
>
>
> Thanks,
>
>
>
> pete bonate
>
>
>
> Peter L. Bonate, PhD, FCP
>
> Genzyme Corporation
>
> Senior Director, Pharmacokinetics
>
> 4545 Horizon Hill Blvd
>
> San Antonio, TX 78229 USA
>
> [EMAIL PROTECTED]
>
> phone: 210-949-8662
>
> fax: 210-949-8219
>
> blackberry cell: 210-315-2713
>
>
>
> --
>
> Paul R. Hutson, Pharm.D.
>
> Associate Professor
>
> UW School of Pharmacy
>
> 777 Highland Avenue
>
> Madison WI 53705-2222
>
> Tel 608.263.2496
>
> Fax 608.265.5421
>
> Pager 608.265.7000, p7856
>
> References
>
> 1. mailto:[EMAIL PROTECTED]
--
Alison Boeckmann
[EMAIL PROTECTED]