NONMEM Users Network Archive

Hosted by Cognigen

Metabolite models

From: Mulla Hussain - Paediatric Medicines Research <hussain.mulla>
Date: Tue, 4 Jan 2011 16:01:47 -0000

Hi

 

We are conducting a pragmatic pop-pk study following a single
extravascular dose of an opioid in children. The parent molecule is
rapidly hydrolysed to metabolite 1, which is subsequently hydrolysed to
metabolite 2. Metabolite 2 is metabolised to metabolite 3 and 4, but
also partially renally excreted. The plasma is being bioanalysed for
metabolite 1 to 4, but not the parent (latter has a half-life of 2-3
mins, and is not known to contribute significantly to PD). Typically, we
are managing to get between 3- 4 samples per subject and hope to recruit
approx. 75 children.

 

We are part way through the study and have done an interim bioanalysis.
I have two model development questions as I plan my analysis:-

 

1. Since parent is not being measured, how would you parameterise
the formation of metabolite 1? i.e. since the appearance of metabolite 1
is a 'two-step' process, absorption of drug and subsequent hydrolysis,
would you consider using previous literature reported estimates of
absorption rate to estimate formation clearance of metabolite 1, or is
it more sensible to estimate the composite parameter (absorption +
formation clearance)?

 

2. It is clear from the interim bioanalysis, that we are not
sampling our far enough to observe the elimination phase of metabolite 3
and 4 i.e. I'm only seeing accumulation. This is a pragmatic hospital
study so it is unlikely that I can persuade the clinicians / nurses /
patients to generate later samples. With that in mind is there any
mileage in including metabolite 3 and 4 in the model?

 

Regards

 

Hussain

 

 

Hussain Mulla

Senior Research Pharmacist

Department of Pharmacy

University Hospitals of Leicester NHS Trust

Glenfield Hospital

Groby Road

Leicester

LE3 9QP

 

Tel: 0116 2502708

 

This e-mail, including any attached files, may contain confidential and /=
 or privileged information and is intended for the exclusive use of the a=
ddressee(s) printed above. If you are not the addressee(s), any unauthori=
sed review, disclosure, reproduction, other dissemination or use of this =
e-mail, or taking of any action in reliance upon the information containe=
d herein, is strictly prohibited. If this e-mail has been sent to you in =
error, please return to the sender. No guarantee can be given that the co=
ntents of this email are virus free - The University Hospitals of Leicest=
er NHS Trust cannot be held responsible for any failure by the recipient(=
s) to test for viruses before opening any attachments. The information co=
ntained in this e-mail may be the subject of public disclosure under the =
Freedom of Information Act 2000 - unless legally exempt from disclosure, =
the confidentiality of this e-mail and your reply cannot be guaranteed. C=
opyright in this email and any attachments created by us remains vested i=
n the University Hospitals of Leicester NHS Trust.

Received on Tue Jan 04 2011 - 11:01:47 EST

The NONMEM Users Network is maintained by ICON plc. Requests to subscribe to the network should be sent to: nmusers-request@iconplc.com.

Once subscribed, you may contribute to the discussion by emailing: nmusers@globomaxnm.com.