RE: associatin/dissociation model
From: "Perez Ruixo, Juan Jose [PRDBE]" JPEREZRU@PRDBE.jnj.com
Subject: RE: [NMusers] associatin/dissociation model
Date: Thu, 6 Oct 2005 14:09:32 +0200
Dear,
The model you described has been also called "target mediated drug
disposition model". From the information you provide, it's very difficult to
provide you with a clear answer. In fact, I've more questions than
clarifications.....:-). Hope you don't mind.
In my experience, it's very difficult to have enough information in the data
to estimate independently Kon, Koff, KETV and the turnover parameters of the
target (or receptor). Did you perform a sensitivity analysis to evaluate
what are the parameters of your model that can be identified given the
information you have?
I would suggest you to include IV data (if available). Just SC data might
not be good enough to fully characterize this complex model.
Also, I assume the bioassays used allow you to quantify the free drug. Do
you have observations from the A(4)? If that's the case, it should be
incorporated in the database and fit together with the free drug
concentrations. This information is critical to estimate the receptor
turnover.
Do you have prior information about the target (receptor) binding and
elimination of the drug receptor complex? If you have it, you could try to
fix Koff and/or KETV to the values obtain from previous (in vitro)
experiments. However, I'm not a big fan of that approach.
I personally prefer the "quasi-equilibrium" approach that has been recently
published [Mager DE, Krzyzanski W. Quasi-equilibrium pharmacokinetic model
for drugs exhibiting target-mediated drug disposition. Pharm Res. 2005
Oct;22(10):1589-96]. With that approach, NONMEM runs are faster and the
difference in parameter estimates and model predictions between the full
model and the quasi-equilibrium model are acceptable in most of the cases.
Hope it helps.
Juan Jose Perez Ruixo, PhD.
Principal Scientist. Advanced PK/PD Modelling & Simulation,
Global Clinical Pharmacokinetic and Clinical Pharmacology,
Johnson & Johnson Pharmaceutical Research & Development,
a Division of Janssen Pharmaceutica, NV.
* Turnhoutseweg 30, B-2340 Beerse, Belgium.
* jperezru@prdbe.jnj.com