From: Rosenborg, Johan <*Johan.Rosenborg*>

Date: Tue, 24 Jun 2008 17:13:40 +0200

Mark,

Thank you very much for your suggestion, we pursued similarly adapted =

for our purposes. Two-compartment models were fitted to the separate =

stereoisomers. The total concentration was modelled as the sum the =

differentials for central and peripheral compartments of the separate =

stereoisomers. Note that three different doses must be given in the data =

set, one for each stereoisomer and one for the sum.

/ Johan

-----Original Message-----

From: Penney, Mark S

Sent: 19 juni 2008 13:43

To: Rosenborg, Johan

Subject: RE: [NMusers] Joint model fitting to data on separate

enantiomers and enantiomeric mixtures

Dear Johan,

I've used the attached control stream (and data file) to estimate =

parameters for a not too disimilar situation.

The model is of the drug (antibody - 2 compartments) and its target =

ligand. We measure two things, the free antibody and the so-called total =

ligand, which is the summation of the free ligand and that bound to the =

antibody. This is measured by an ELISA where the capture antibody =

recognises an epitope that is remains available after binding with the =

therapeutic antibody. I use an IF statement in the $ERROR block to pick =

what was measured based on the value of CMT in the data file.

The aim of the run is to pick up the kinetics of the ligand, which turns =

over quite quickly in comparison to the slowly-cleared antibody. I had a =

mixture of i.v. and sub-cut administration too.

I used ADVAN8 because it was the only one that could apparently solve =

the problem. I had a lot trouble getting NONMEM to run this, hence the =

simplifying of all the ETAs fixed to 0.0 and the assumption of the same =

error for the two assays. Got what I needed though.

Regards,

Mark

-----Original Message-----

From: owner-nmusers

[mailto:owner-nmusers

Sent: 18 June 2008 15:28

To: nmusers

Cc: Johansson, Anna X

Subject: [NMusers] Joint model fitting to data on separate enantiomers

and enantiomeric mixtures

All,

We have a data set comprising three measurements per time point, namely =

the separate R- and S-concentrations and the total concentration (R+S) =

of a chiral drug given as the racemic mixture. We would like to fit a =

model to all data simultaneously. The plan is to estimate one set of =

parameters for the S- enantiomer and one set for the R- enantiomer, =

using the sum of S- and R concentrations to predict R+S; defining CMTs =

1, 3, and 5 as observational compartments for R-, S-, and RS, =

respectively, we would like to model A(5)=A(1)+A(3). Any suggestion on =

how to do proceed with this in ADVAN5 or ADVAN6 would be appreciated!

/ Johan and Anna

Received on Tue Jun 24 2008 - 11:13:40 EDT

Date: Tue, 24 Jun 2008 17:13:40 +0200

Mark,

Thank you very much for your suggestion, we pursued similarly adapted =

for our purposes. Two-compartment models were fitted to the separate =

stereoisomers. The total concentration was modelled as the sum the =

differentials for central and peripheral compartments of the separate =

stereoisomers. Note that three different doses must be given in the data =

set, one for each stereoisomer and one for the sum.

/ Johan

-----Original Message-----

From: Penney, Mark S

Sent: 19 juni 2008 13:43

To: Rosenborg, Johan

Subject: RE: [NMusers] Joint model fitting to data on separate

enantiomers and enantiomeric mixtures

Dear Johan,

I've used the attached control stream (and data file) to estimate =

parameters for a not too disimilar situation.

The model is of the drug (antibody - 2 compartments) and its target =

ligand. We measure two things, the free antibody and the so-called total =

ligand, which is the summation of the free ligand and that bound to the =

antibody. This is measured by an ELISA where the capture antibody =

recognises an epitope that is remains available after binding with the =

therapeutic antibody. I use an IF statement in the $ERROR block to pick =

what was measured based on the value of CMT in the data file.

The aim of the run is to pick up the kinetics of the ligand, which turns =

over quite quickly in comparison to the slowly-cleared antibody. I had a =

mixture of i.v. and sub-cut administration too.

I used ADVAN8 because it was the only one that could apparently solve =

the problem. I had a lot trouble getting NONMEM to run this, hence the =

simplifying of all the ETAs fixed to 0.0 and the assumption of the same =

error for the two assays. Got what I needed though.

Regards,

Mark

-----Original Message-----

From: owner-nmusers

[mailto:owner-nmusers

Sent: 18 June 2008 15:28

To: nmusers

Cc: Johansson, Anna X

Subject: [NMusers] Joint model fitting to data on separate enantiomers

and enantiomeric mixtures

All,

We have a data set comprising three measurements per time point, namely =

the separate R- and S-concentrations and the total concentration (R+S) =

of a chiral drug given as the racemic mixture. We would like to fit a =

model to all data simultaneously. The plan is to estimate one set of =

parameters for the S- enantiomer and one set for the R- enantiomer, =

using the sum of S- and R concentrations to predict R+S; defining CMTs =

1, 3, and 5 as observational compartments for R-, S-, and RS, =

respectively, we would like to model A(5)=A(1)+A(3). Any suggestion on =

how to do proceed with this in ADVAN5 or ADVAN6 would be appreciated!

/ Johan and Anna

Received on Tue Jun 24 2008 - 11:13:40 EDT