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The following message was posted to: PharmPK
Hi everybody
I am wondering if one can model data that shows flipflop kinetics in
WinNonlin using one the library models. Also, is it possible to get a
plot of the "feathered" curve. Thanks.
-Saileta
Saileta Prabhu, Ph.D.
Scientist
ADME-PK
Sunesis Pharmaceuticals
341 Oyster Point Blvd
South San Francisco, CA 94080
Tel.: 650-266-3679
Fax: 650-266-3502
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Dear Saileta,
I have some idea about modelling data using winnonlin. Any one in the
group please correct me if i am wrong.
Flipflop kinetics: The diagnostic for this kind of data:
(i)If the terminal portion of the conc. time curve is not parallel for
Oral and IV data.
(ii) If Ka (Absorption rate constant) is less than Ke (Elimination rate
constant)
Calculate the initial estimates i.e., V/F, K01, K10, Lag time from your
conc. time profile. Initially by looking at K01 & K10 values you can
guess whether it undergoes flipflop kinetics; Then use model 4 - from
the winnonlin compiled models (I am assuming that your compound shows
one compartment behaviour). In the results look at your observed and
predicted profile, Std error, CV(%) and some other statistical
parameters like AIC, SS, WRSS and condition no. based on that we will
know whether the model fits the data well or not.
For the same data if you fit with model 5 and model 6 which is for
K01=K10 with and without lag time, the model fails. Hope this will help.
Thanks,
B.L.Suresh
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Dear Saileta:
Why do you want to use a basically obsolete method like
feathering? Why don't you consider using more up to date methods? Most
population modeling software will do a much better job on the data, and
nonparametric pop modeling such as NPAG currently appears to be the
best, as it is consistent, and not restricted by assumptions of normal
or lognormal parameter distributions. You can go to www.lapk.org, and
click on new advances in population modeling, and see Bob Leary's
careful simulation study about this.
Very best regards,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine,
Division of Geriatric Medicine,
Laboratory of Applied Pharmacokinetics,
USC Keck School of Medicine
2250 Alcazar St, Los Angeles CA 90033, USA
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.-a-.usc.edu
Our web site= http://www.lapk.org
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The following message was posted to: PharmPK
Dear colleagues,
Dr. Suresh wrote:
> Flipflop kinetics: The diagnostic for this kind of data:
> (i)If the terminal portion of the conc. time curve is not parallel for
> Oral and IV data.
OK
> (ii) If Ka (Absorption rate constant) is less than Ke (Elimination
> rate constant)
If you have only oral (or any extravascular) data, there are always two
solutions for the model parameters. In case of a one-compartment model,
the values of k01 (or ka, absorption rate constant) and k10 (or ke,
elimination rate constant) can always be interchanged, resulting in
exactly the same plasma profile. The solutions where k01 > k10 is
usually regarded as the 'normal' solution, and the solution where k01 <
k10 as 'flip-flop'. Note that the value of V/F is different for both
solutions.
Which of the two solutions is obtained, depends primarily on the
software, and probably of the initial estimates of the parameters. E.g.
using initial estimates k01 > k10 will likely result in a solution
where k01 > k01, but this is not necessarily so. The major point here
is that there is no way to decide which solution reflects best the real
situation. Looking at the values of k01 and k10 does not solve the
problem! Since the 'flip-flop' may be true in the analysis of any
extravascular data, I would say that a fitting program should always
provide both solutions. If the user has additional information, he/she
may choose the most likely solution. The common practice of using the
solution where k01 > k10 is highly questionable.
If oral and iv data are available, simultaneous fitting solves the
problem completely. Actually there is no need to use the term
'flip-flop' since there is only one solution, and nothing is flipping
or flopping.
> Calculate the initial estimates i.e., V/F, K01, K10, Lag time from
> your conc. time profile. Initially by looking at K01 & K10 values you
> can guess whether it undergoes flipflop kinetics;
As stated above, looking at the values does not solve the problem.
> In the results look at your observed and predicted profile, Std error,
> CV(%) and some other statistical parameters like AIC, SS, WRSS and
> condition no.
As stated above, the plasma profile of both solutions is exactly the
same, and so are the statistical parameters.
Best regards,
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.aaa.farm.rug.nl
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