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Re: VD as a fraction of another VD

From: Nick Holford <n.holford>
Date: Tue, 22 May 2012 15:33:21 +0200

Carlos,

The Knibbe morphine/metabolite model has no pharmacological
justification for fixing the metabolite volume to a fraction of the
parent. It is an empirical model with other unusual assumptions such as
making central and peripheral volumes equal to each other. It is also
claimed that clearance of morphine by other routes than to M3G and M6G
was negligible but in fact is is impossible to draw such a conclusion
from this kind of data.

I would suggest you stick to models which recognize the limitations of
estimating metabolite parameters when only parent drug is administered
e.g. Bouwmeester et al. 2004).

Best wishes,

Nick

Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Developmental
pharmacokinetics of morphine and its metabolites in neonates, infants
and young children. Br J Anaesth 2004; 92: 208-17.


On 22/05/2012 6:41 a.m., Carlos Orlando Jacobo Cabral wrote:
> Dear Nick,
>
> I want to try a previously reported PK model (Knibbe /et al. /Clin
> Pharmacokinet 2009; 48 (6): 371-385) to fit data similar to mine of
> morphine and its metabolites in which the volumes of distribution of
> metabolites were estimated as a fraction of volume of parent drug what
> seems to show good estimates. But also probably I´ll try to estimate
> the volumes of metabolites as separate parameters THETA with its
> corresponding variabilities, do you have any other suggestions?, thank
> you.
> And thanks also to Billand Rob.
>
> Kind regards,
>
> Orlando.
>
> /P//hD //student/ Carlos Orlando Jacobo Cabral
>
> Departamento de Farmacología, Lab.34
>
> Centro de Investigación y de Estudios Avanzados del I. P. N.
>
> Email: orlandofly
> cjacobo
>
> ---------------------------------------------------------------------------------------------------------
>
>
>
>
>
> > Date: Mon, 21 May 2012 22:12:18 +0200
> > From: n.holford
> > To: nmusers
> > Subject: Re: [NMusers] VD as a fraction of another VD
> >
> > Carlos,
> > Why? What pharmacological or physiological reason would lead you to
> want
> > to fix the volume of a metabolite to be a fraction of the parent?
> > Nick
> >
> > On 21/05/2012 8:19 p.m., Carlos Orlando Jacobo Cabral wrote:
> > > Dear NMusers,
> > >
> > > Hi, I have data of a parent drug (intravenously administered) and its
> > > metabolite, ¿How can I code the volume of distribution of metabolite
> > > as a fraction of the central volume of parent?
> > > An example of the model that I want to fit is:
> > >
> > > $PK
> > >
> > > V1=THETA(1)*EXP(ETA(1)) ; Central Volume of parent
> > > V2=THETA(2)*EXP(ETA(2)) ; Peripheral Volume of parent
> > > Q=THETA(3) ; intercompartmental clearance
> > >
> > > V3= ???????????? ; Volume of metabolite as a fraction of V1 with
> > > variability
> > >
> > > CL1=THETA(5)*EXP(ETA(4)) ; Formation clearance of metabolite
> > > CL2=THETA(6)*EXP(ETA(5)) ; Elimination clearance of metabolite
> > > CL0=THETA(7)*EXP(ETA(6)) ; Parent drug excretion by routes other than
> > > formation of metabolite
> > >
> > >
> > >
> > > - Thank you in advance.
> > >
> > > Orlando.
> > >
> > > /P//hD //student/ Carlos Orlando Jacobo Cabral
> > >
> > > Departamento de Farmacología, Lab.34
> > >
> > > Centro de Investigación y de Estudios Avanzados del I. P. N.
> > >
> > > Email: orlandofly
> > > cjacobo
> > >
> >
> > --
> > Nick Holford, Professor Clinical Pharmacology
> >
> > First World Conference on Pharmacometrics, 5-7 September 2012
> > Seoul, Korea http://www.go-wcop.org
> >
> > Dept Pharmacology& Clinical Pharmacology, Bldg 505 Room 202D
> > University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
> > tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53
> > email: n.holford
> > http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
> >
> >
> >

--
Nick Holford, Professor Clinical Pharmacology

First World Conference on Pharmacometrics, 5-7 September 2012
Seoul, Korea http://www.go-wcop.org

Dept Pharmacology& Clinical Pharmacology, Bldg 505 Room 202D
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53
email: n.holford
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford


Received on Tue May 22 2012 - 09:33:21 EDT

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