RE: VD as a fraction of another VD
Dear Orlando,
There are multiple models available for morphine in children younger than
three years. The model by Knibbe is based on a data-driven analysis, which
causes this model to be empirical, but supported by the data. In addition to
that and very importantly the Knibbe model is the only model that was proven
to have accurate model performance in extensive internal and external
validation procedures. (Clin Pharmacokinet. 2011 Jan;50(1):51-63 & Pharm
Res. 2011 Apr;28(4):797-811)
Based on the available data, it was not possible to determine the
distribution volume of the metabolites in the model. This would require data
on the metabolites after direct intravenous infusion of the metabolites, but
this is unethical and therefore not possible in children. We were therefore
bound to include assumptions in our model. We have chosen to estimate the
distribution volumes of the metabolites as a proportion of the central
morphine compartment using the following code:
V1 = THETA(1)*EXP(ETA1) ; central volume for morphine
V2 = THETA(2)*V1 ; volume for M3G
By using only 1 eta, we made the implicit assumption that the
inter-individual variability in the volume of the metabolites is
proportional to the variability in the central volume of morphine. This
assumption cannot be proven or disproven with the available data, but to us
it does not seem to be too unrealistic to envision that if one of the
volumes increases or decreases the others will proportionally increase or
decrease as well.
Additionally, we found that when estimating the fraction for M3G and M6G
independently, their 95% confidence interval overlapped significantly and
the same was true for the distribution volume of the peripheral and central
compartment of morphine. According to the rule of parsimony these parameters
were therefore set to be equal.
V3 = V2 ; volume for M6G equal to volume M3G
V4 = V1 ; peripheral volume morphine equal to central volume
For both adults and children morphine elimination through routes other than
glucuronidation has been reported. In our model, with our assumptions, we
found that when estimating a clearance parameter for elimination through
other routes, 0 was included in 95% confidence interval of this parameter.
According to the rule of parsimony we therefore did not include this
parameter in the model. I would suggest that for your data you test
inclusion of this parameter and decide based on statistical criteria and
validation of your model whether you retain it or not.
Regards,
Elke
_____
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Carlos Orlando Jacobo Cabral
Sent: Tuesday, May 22, 2012 6:42 AM
To: nonmem users
Subject: RE: [NMusers] VD as a fraction of another VD
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 Bill and Rob.
Kind regards,
Orlando.
PhD student Carlos Orlando Jacobo Cabral
Departamento de Farmacología, Lab.34
Centro de Investigación y de Estudios Avanzados del I. P. N.
Email: [email protected]; [email protected]
----------------------------------------------------------------------------
-----------------------------
> Date: Mon, 21 May 2012 22:12:18 +0200
> From: [email protected]
> To: [email protected]
> 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: [email protected] <mailto:[email protected]>;
> > [email protected] <mailto:[email protected]>
> >
>
> --
> 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: [email protected]
> http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
>
>
>