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Simutaneously fitting IV and SC data


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#1 Wendy Cai

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Posted 08 February 2012 - 05:26 PM

Hi Simon,

I use the graphical tool to build a model for the simutaneously fitting of both IV and SC data and calculation of PK parameters including bioavailability. Here is the test for the model:

test(){
deriv(A1 = - (Cl * C)- (Cl2 * (C - C2)) + (Aa * Ka))
urinecpt(A0 = (Cl * C))
deriv(A2 = (Cl2 * (C - C2)))
deriv(Aa = - (Aa * Ka))
C = A1 / V
dosepoint(A1, idosevar = A1Dose, infdosevar = A1InfDose, infratevar = A1InfRate)
C2 = A2 / V2
error(CEps = 1)
observe(CObs = C * (1 + CEps))
dosepoint(Aa, bioavail = (F), idosevar = AaDose, infdosevar = AaInfDose, infratevar = AaInfRate)
stparm(V = tvV * exp(nV))
stparm(Cl = tvCl * exp(nCl))
stparm(V2 = tvV2 * exp(nV2))
stparm(Cl2 = tvCl2 * exp(nCl2))
stparm(Ka = tvKa * exp(nKa))
stparm(F = tvF * exp(nF))
fixef(tvV = c(, 2936, ))
fixef(tvCl = c(, 238, ))
fixef(tvV2 = c(, 2852, ))
fixef(tvCl2 = c(, 859, ))
fixef(tvKa = c(, 1.28, ))
fixef(tvF = c(, 0.77, ))
ranef(diag(nV, nV2, nCl, nCl2, nKa, nF) = c(1, 1, 1, 1, 1, 1))
}


However, the bioavailability result does not make sense. It is over 100%. I know the BA is about 80% using the NCA analysis. A file with text and graph model is attached. Do you see any errors in the model text and graph?

Thanks for the help!

Wendy
/extranet/media/kunena/attachments/legacy/images/model_image.jpg

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  • model_image.jpg
  • model_image-20120209.jpg
  • model_image-20120209-3.jpg
  • work1.jpg

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#2 Simon Davis

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Posted 09 February 2012 - 10:32 PM

Hi Wendy,

 

   From the Phoenix model you sent, F is only 1.03 with 6% SE - so not outrageous.

 

 We suggest you use the ilogit transform for the F parameter. Get a table of the structural parameters. The nF shrink to zero for the IV doses, so that is the value of tvF.

 

  Simon.



#3 Simon Davis

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Posted 10 February 2012 - 06:58 PM

Hi Wendy, did you manage to get this working OK? Posted Image

I ended up running the Naive pool method to refine my initial estimates as my first run with FOCE-LB ended with a Return code of -1. Once I accepted those results, as inital estimates I re-ran with FOCE-ELS and got a pop estimate of F at 0.88, here is the table [file name=Table01.xls size=10240]http://pharsight.com/extranet/media/kunena/attachments/legacy/files/Table01.xls[/file]

or you can use the custom transformation to convert the inverse logistic tvF back again;

1/(1+exp(-tvF))

Have a good w/e. Simon

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#4 Wendy Cai

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Posted 10 February 2012 - 09:00 PM

Hi Simon,

 

Yes,I got it working.

 

Thanks for the help!

 

Wendy



#5 StineOttesen

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Posted 20 November 2017 - 12:54 PM

Hi Simon,

I have related questions to this old thread:

When you estimate absolute bioavailability (when having for instance IV and SC adminsitrations as in this data set), is it then correct that the estimated parameters provided in the table "Theta" are for SC administration? Thus, they are actually CL/F, V/F etc.?

Is there an obtion in NLME where you can choose to get the IV parameters instead so you don't have to multiply by F?

Thanks

Stine


Hi Wendy, did you manage to get this working OK? ilogit.jpg

I ended up running the Naive pool method to refine my initial estimates as my first run with FOCE-LB ended with a Return code of -1. Once I accepted those results, as inital estimates I re-ran with FOCE-ELS and got a pop estimate of F at 0.88, here is the table [file name=Table01.xls size=10240]http://pharsight.com/extranet/media/kunena/attachments/legacy/files/Table01.xls[/file]

or you can use the custom transformation to convert the inverse logistic tvF back again;

1/(1+exp(-tvF))

Have a good w/e. Simon



#6 Simon Davis

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Posted 20 November 2017 - 02:07 PM

Hi Stine, the model parameters are ‘true’ V, CL etc. and the F corrects the predictions when it's extravascular dosing.

 

I.e. if you were to simulate an IV you would use the V and CL directly.

 

 Simon.



#7 StineOttesen

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Posted 21 November 2017 - 10:15 AM

Thanks, Simon.

Some follow up questions:
What about the Posthoc table for the individual parameter values? Will that table also contain the IV parameters for all subjects, also those receiving only SC?

In the data set I am working on, the posthoc table contains ka values for all subjects. How is that estimated for subjects only receiving IV dosing?

Thank you.

#8 Simon Davis

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Posted 21 November 2017 - 11:48 AM

Hmm - not sure why you have  post-hoc estimate for Ka when only received IV,  I guess it's a prediction of what it might be.   Would it be possible to post the project, or something representative and I'll have a look.  If confidentiality is a concern you could alternatively email Support, referencing this conversation.






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