9 replies to this topic

[Elliot Offman]

Has anyone attempted to fit only extravascular administration to 3 Ka or 2 Ka and zero input?

I'm wondering how that would be expressed in terms of relative bioavailability?

I understand how to do 2 Ka or 1 Ka and 1 zero input using F and 1-F, but does anyone know if with only the extravascular doses if you can identify the 3 Kas and how the relative F would be expressed for each of the 3 rates when there isn't IV?

thanks

Elliot

[serge guzy]

Dear Elliot

I think we have here 2 different options. The fraction that would go with one Ka and the bioavailability. For pure bioavailability issues, you would need both IV and oral. however for multiple Ka's if the data support it, it could be identifiable. Suppose you have 2 Ka's and the first absorption occurs immediately while the second has a tlag. You should be able to differentiate the 2 Ka's. Now what do you mean by zero order input? If you have a Ka, it is first order input. Can you share the data?

best

Serge

[Elliot Offman]

Thanks for the rapid reply. I can't share all the data at this time, but I've attached a representative PK profile of what I'm attempting to model.
So far best fit zero order for a short duration with bioavailability of F directly into the central compartment followed by a first order with a lag time and bioavailaility of 1-F from an absorption compartment.

although its the best fit my VPC suggests that the peak is not getting characterized sufficiently. So I wanted to evaluate the impact of an additional Ka.

Thoughts?

[serge guzy]

Dear elliott

You can add an additional extravascular compartment with tlag and define the additional fraction. You need to pay attention that the overall percent of drug is 100 percent because younhave 3 fractions. Try and let me know.

Best

Serge

[Elliot Offman]

Hi,

yes, the 3 fractions I get, but I am not sure how to write that in PML.

Ive for F total = 1

where F= F1+F2+F3

 

I understand how to do it with 2 dosepoints where the bioavail = F for the first one and 1-F for the second dosepoint, but not clear on how it works with 3 dosepoints.

 

I'm thinking in terms of dosepoint statements like:

dosepoint(Aa, bioavail = 1-(F2+F3)

dosepoint(Aa2, bioavail = ......)

dosepoint(Aa3, bioavai = ......)

 

And then how to express it in terms of fitted parameters.

 

thanks

Elliot

[Elliot Offman]

I think I figured this out but want to make sure it makes sense so if anyone has any comments I'd appreciate it.
for dosepoint statements
Dosepoint (Aa, bioavail=F1, ….)
Dosepoint (Aa2, bioavail = (1-F1)*F2, tlag=tlag,…etc….
Dosepoint (Aa3, bioavail = 1-F1-[(1-F1)*F2), ...etc...

Then have two fitted parameters F1 and F2 where F3is a derived parameter = 1-(F1+F2).

i've set this up using the graphical interface like this:

[serge guzy]

Dear Elliott

I think there are still issues you need to be aware of.

 

Suppose

 

Dosepoint (Aa, bioavail=F1, ….)

Dosepoint (Aa2, bioavail = (1-F1)*F2, tlag=tlag,…etc….

Dosepoint (Aa3, bioavail = 1-F1-[(1-F1)*F2), ...etc

 

 

F1 =0.2

F2=0.8

 

Then fraction in Aa is 0.8

Fraction in Aa2 is 0.8*0.8==0.64

Fraction in Aa3 is 1-0.8-0.64

 

You see the problem. You overshooted. F1+F2 >1 and F3 is negative.

Then the best way to do it is to add in edit as textual constraints on THESE FRACTIONS to prevent any negative fraction to be recorded..

[Elliot Offman]

Yes, thanks, I see that. I

so I've put some constraints on the F1 and F2 so the sum cannot exceed 1 and none will be negative.

thanks for verifying my code!

Elliot

[Elliot Offman]

Hi,

just wanted follow-up on this to let the know this approach did indeed bear fruit.The absorption phase fits much better using this parallel ka with zero order input. The sum of the fractions from the 3 different routes =1

Elliot

[serge guzy]

Great to hear.

Best

Serge