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I have a problem to discuss some of my results when I
used the Scientist (Pharmacokinetic Program) to fit my
set data (when oral administration was used). A two
compartment open model was used to fit the data.
Statistic showed a MSC value over 2 with fator 1. The
fit was very good with a good correlation .
IndVars: T
DepVars: c
Params: a,b,d,alfa,beta,delta
C=(a*(exp(-alfa*t)))+(b*(exp(-beta*t)))-(d*(exp(-
delta*t)))
C is the same that A+B, C>A>B, gama>alfa>beta
After least Squares fit the values of A and C were very
large and almost the same, very different from the
middle values obtained.
C = A+B must be always true???
What can I do?
Any help that you could provide would be greatly
appreciated.
Best Regards,
Leandro Tasso
Laboratório de Farmacocinética
Programa de Pós Graduação em Ciências Farmacêuticas
Universidade Federal do Rio Grande do Sul
Av. Ipiranga, 2752, 90610-000
Porto Alegre-RS/Brasil
Fone: +55-51-3316-5215
e-mail: letasso.-a-.bol.com.br
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The following message was posted to: PharmPK
Dear Leandro Tasso,
You wrote:
> IndVars: T
> DepVars: c
> Params: a,b,d,alfa,beta,delta
> C=(a*(exp(-alfa*t)))+(b*(exp(-beta*t)))-(d*(exp(-
> delta*t)))
> C is the same that A+B, C>A>B, gama>alfa>beta
> After least Squares fit the values of A and C were very
> large and almost the same, very different from the
> middle values obtained.
> C = A+B must be always true???
I trust that you mean 'd' instead of 'C' here since C refers to the
concentration? The minus sign in the equation suggests that 'delta' is
the
absorption rate constant (ka)?
In my experience it occurs rather often that ka and k (in case of
one-compartment) or alpha or beta (in case of two compartments) become
almost similar. As a results their coefficients a (or b) and d become
very
large, since this value is a composite value that can written as
F.Dose/V .
ka/(ka-k) (or a slightly different equation for two compartments).
I wrote a message to the PharmPK group several years ago, but i did not
get
a fully satisfactory response. From Monte Carlo simulation I learned
that
this happens rather often, also in cases where the true values for ka
and k
(or a or b) differ by a factor of, say, 2. Please note that
computational
problems may at least affect the problem. If ka and k are almost equal,
both
parameters become strongly correlated, and cannot be estimated
accurately.
But reparametrization does not solve the problem.
I still do not know why this happens so often. Any suggestion is
welcome!
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-at-.farm.rug.nl
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The following message was posted to: PharmPK
Dear Dr. Tasso,
I read your post recent post regarding Scientist and forwarded the data
you provided to our technical support team. They have confirmed your
initial result (i.e. the convergence and solution you have inquired
about). After taking the following actions to adjust the initial
parameters as follows we they have obtained the following results which
appear to be more consistent:
If you edit rat3.par to reflect initial estimates corresponding to the
middle.par (A = 4.3106, B = 1.7903, D = 6.1294, ALFA = 0.65985, BETA =
0.070391, KA = 3.3189) and then perform a fit, you end up with fitted
estimates of A = 5.0608, B = 0.45005, D = 5.4789, ALFA = 0.26611, BETA =
4.4382e-17, KA = 6.5629. This seems more in line with what is accepted.
Of
course, the BETA value suggests that the concentration B is nearly
constant. But looking at middle.par, we see that BETA = 0.070391, so a
near zero value seems within tolerable experimental error.
It appears that your initial paramerter estimates converged on a
solution
that is physically unlikely. We will look at putting some additional
validation routines into our new version of Scientist (MicroMath
Scientist
3.0) scheduled for release this fall.
Thank you for your business.
Christopher A. Thornton
Manager, MicroMath Research
1710 South Brentwood Blvd.
Saint Louis, Missouri 63144
1.800.942.6284
www.micromath.com
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)