Identify the dose-to-metabolite ratio.

Phoenix Certara Forums Modelling and Simulation
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I’m developing a model in which the parent drug is metabolized to an active metabolite and a portion of the oral dose is metabolized in the GI to the active metabolite. I am trying to model the amount that is metabolized from the dose in addition to remaining amount goes to the central compartment of the parent drug.

I found this model created by one member who tried to build the structural model using graphical model, however, he did not account for fraction of the dose went to the parent and metabolite compartments.

Can I get help on how to model the fraction formed?

I am attaching the model and a schematic description of a model that shows the structural model details.

M&S_070616.phxproj (649 KB)Sunitinib_Parent_Metabolite_Model.docx (37.9 KB)

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try to write your model in textual mode:
from you schema

you split the dose between Aa and Ap directly to parent both using the same Kapar

you will need a copy of your dosing column or a special mapping by hand

dosepoint(Aa, bioavail = (F), idosevar = AaDose, infdosevar = AaInfDose, infratevar = AaInfRate)
dosepoint(Ap, bioavail = (1-F), idosevar = AaDose, infdosevar = AaInfDose, infratevar = AaInfRate)

#you can then write your equation making sure you split your clearances as you see fit

deriv(Aa = - (Aa * Kapar))
deriv(Am = - (Am * Kapar))

deriv(Ap1 = (Aa * Kapar)- (Q * (Cp1 - Cp2))- (fm_sys*CL_sunitinib * Cp1)- ((1-fm_sys)*CL_sunitinib * Cp1))
deriv(Ap2 = (Q * (Cp1 - Cp2)))

deriv(Am1 = (Am * Kapar) + ((1-fm_sys)*CL_sunitinib * Cp1)- (CLm1 * Cm1)- (CLm2 * (Cm1 - m2)))
deriv(Am2 = (CLm2 * (Cm1 - m2)))

code not tested make sure to double check also not sure your metabolite you want it 1 or 2 cmt

3

Thanks a lot, Sameer.

Your explanation about splitting the clearance was extremely helpful. I still have a question about the parent-to-metabolite ratio.

I’m attempting to estimate different absorption rate constants, one for the parent drug and another for the metabolite, as follows:

Kp = parent drug absorption rate constant from depot to central compartment of parent drug

Km = constant absorption rate of metabolite drug from depot to central compartment of metabolite

It should be similar to the structural model I’m attaching, which estimates both Kp and Km.

Thank you!!

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4

before fitting such models make sure that they are locally identifiable but to answer you question

you will need to work in molar since these are two distinct compounds and you are dosing atorvastatin in depot

yet your are absorbing into atorvastatin metabolite so question for how are you converting the initial dose of atorvastatin into hydroxy Metabolite ?

you can split the dose into two depot with Frel and 1- Frel to miminck this model

phoenix allow you to have mutliple dose point or split into one depot cmpartment or you can have mutliple depot (this require you to have a copy of your dose into a separate column) so you can dose say Frel *dose into depot parent and 1-Frel into depot metabolite

notice the split modifier :

dosepoint(Aa, bioavail = (Frel), idosevar = AaDose, infdosevar = AaInfDose, infratevar = AaInfRate, split)
dosepoint2(Aa, bioavail = (1-Frel))

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Thanks Sammer for your explanation.

In terms of converting the dose to the metabolite compartment. I used the attached model, which used an absorption parameter (K preM) that went directly from the dose compartment to the metabolite compartment. The addition of this step improved the fit of the metabolite but resulted in underestimation of the parent drug’s PK parameters.

Thanks

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