NONMEM Users Network Archive

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RE: [NMusers] Unable to achieve Cmax

From: Martin Bergstrand <martin.bergstrand_at_pharmetheus.com>
Date: Fri, 8 Dec 2017 10:39:33 +0100

Dear Anuja,



First of all, having 1-compartment distribution for some subjects and
2-compartment distribution for others rarely makes any sense. If this is
what you are using I would really suggest to get rid of that.



Below you will find an answer to a similar question regarding “doub=
le peak
absorption” from some years back. This might be a useful starting p=
oint for
you.

http://cognigencorp.com/nonmem/current/2010-October/2054.html



The proposed approach in the above answer can be modified in many ways e.g.

- Add 2-N transit compartments for one or two of the absorption path=
s

- Add a zero-order absorption for one or two of the absorption paths
(see NONMEM user guide for implementation by setting RATE==-1 or RATE=
==-2)



I would propose that you investigate different permutation of this until
you achieve what can be described as an adequate description of the
absorption. It can always get better but be satisfied with you have
something that seems “good enough”.



Notice that with modelling of only oral data it can be difficult to fully
separate absorption and disposition processes (distribution and
elimination). For that reason it is important to look for other information
on the disposition PK for the drug to make sure that the model is
adequately parameterized with regards to distribution (e.g. 1/2/3
distribution compartments) and elimination (e.g. linear v.s. saturable
elimination). This information can come from the literature and/or i.v.
data on file. Prior information about the appropriate model structure
should be used but it may also be necessary to include prior information
about the estimates for parameters with low identifiability given the
design of the experiment (check $PRIOR in the NONMEM used guide).



Best regards,



Martin Bergstrand, Ph.D.

Senior Consultant

Pharmetheus AB



+46(0)709 994 396

martin.bergstrand_at_pharmetheus.com

www.pharmetheus.com



+46(0)18 513 328

U-A Science Park, Dag Hammarskjölds v. 52b

752 37 Uppsala, Sweden



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*From:* owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com] =
*On
Behalf Of *Anuja Dhas
*Sent:* Thursday, December 07, 2017 6:48 AM
*To:* nmusers_at_globomaxnm.com
*Subject:* [NMusers] Unable to achieve Cmax



Dear All,



I am a Beginner for NONMEM. I am having a dataset of oral BE study. The
Drug is BCS III and tmax is 0.5-2hrs. I have observed lag time and double
peak; but I am not assure it is double peak or sampling error. I have used
ALAG in the control file to deal with lag time. The half of the subjects
are following 1 compartmental absorption and the rest are following 2
compartmental absorption. So I separately modeling each compartment. Is it
right method?? Should I use transit model?



The elimination phase is captured well; but I am unable to achieve Maximum
Concentration. The CWRES vs. Time & CWRES vs.PRED plots clearly indicates
bias at high concentration.



Please suggest me some needful actions to deal with these problems.





*Best Regards*

*Anuja*


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Received on Fri Dec 08 2017 - 04:39:33 EST

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