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Metabolite models

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



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?







Hussain Mulla

Senior Research Pharmacist

Department of Pharmacy

University Hospitals of Leicester NHS Trust

Glenfield Hospital

Groby Road




Tel: 0116 2502708


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

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