I've been asked to model zymogen and activated wild type and mutated forms of
an enzyme in in-bred mice.
So one can consider the mutation of the administered protein a covariate, if
you will
For wild-type protein the model is 3 compartment, but when I throw in various
other mutations (8 in all) the model changes from 3- to 2- compartments,
depending upon the mutated protein administered.
Normally we decide what number of compartments (exponents) explains our model,
then look at etas and covariate.
Has anyone set up a model where the base-model fit is 2- vs 3- compartments
depending upon what "drug" (or crystalline form or isotopic formulation) was
administered?
I am hoping that the model for each mutation may be partially explained by its
binding (or lack thereof) to circulating activating or quenching proteins.
Thanks
Paul
Paul R. Hutson, PharmD, BCOP
Distinguished Professor (CHS)
Thora M. Vervoren Professor for Research in Psychoactive Substances
UW School of Pharmacy
Director, UW Madison Transdisciplinary Center for Research in Psychoactive
https://www.research.pharmacy.wisc.edu/tcrps
Faculty Leader, Paul P. Carbone Comprehensive Cancer Center Cancer Pharmacology
https://cancer.wisc.edu/research/resources/ddc/cancer-pharmacology/
T: 608.263.2496
[email protected]
Modeling 2 vs 3 compartments for mutant proteins
Hi Paul,
Yes I have done that in the past in a different context (translational modeling). There is nothing stopping you from coding it by conditionally setting the appropriate rate constants to zero.
But in your case it indeed might be more helpful to build a mechanism-based TMDD model as you stipulate yourself. With enzyme activation forms, substrate and other binding partners that may be more complex but it will add to understanding the fate of the drug.
Hope this helps,
Jeroen
http://pd-value.com [email protected] @PD_value +31 6 23118438 -- More value out of your data!
Quoted reply history
> Op 3 mrt 2026 om 19:57 heeft Paul Hutson <
>
> [email protected]
>
> > het volgende geschreven:
>
>
> I’ve been asked to model zymogen and activated wild type and mutated forms of an enzyme in in-bred mice.
>
> So one can consider the mutation of the administered protein a covariate, if you will
>
> For wild-type protein the model is 3 compartment, but when I throw in various other mutations (8 in all) the model changes from 3- to 2- compartments, depending upon the mutated protein administered.
>
> Normally we decide what number of compartments (exponents) explains our model, then look at etas and covariate.
>
> Has anyone set up a model where the base-model fit is 2- vs 3- compartments depending upon what “drug” (or crystalline form or isotopic formulation) was administered?
>
> I am hoping that the model for each mutation may be partially explained by its binding (or lack thereof) to circulating activating or quenching proteins.
>
> Thanks
> Paul
>
> Paul R. Hutson, PharmD, BCOP
>
> Distinguished Professor (CHS)
>
> Thora M. Vervoren Professor for Research in Psychoactive Substances
> UW School of Pharmacy
>
> Director, UW Madison Transdisciplinary Center for Research in Psychoactive Substances
>
> Faculty Leader, Paul P. Carbone Comprehensive Cancer Center Cancer Pharmacology
> Laboratory
>
> T: 608.263.2496
>
> [email protected]