Back to the Top
The following message was posted to: PharmPK
Dear Listmembers,
I have a question regarding Pharsight's WinNonlin compiled PK models in
which K01 = K10 (e.g., Model #5 in the library). Since I have not seen
these models used much, I was wondering when it would be appropriate to
apply them. Would it be for data with sparse numbers of samples during
the initial absorption phase, for which it is otherwise difficult to
accurately estimate the value of K01?
Thanks
Ronette
Ronette Gehring BVSc, MMedVet (Pharm)
Assistant Professor
Department of Clinical Sciences (Agricultural Practices)
Kansas State University, College of Veterinary Medicine
I 107 Mosier Hall
Manhattan
KS 66506
Telephone: 785-532-2153
E-mail: rgehring.aaa.vet.ksu.edu
Back to the Top
[Sorry if some of the messages are out of order. I've had to retrieve =20
some of the PharmPK messages from my junk mail box. I'm using a =20
different computer and have to retrain the junk filter - db]
The following message was posted to: PharmPK
Dear Ronette!
If WinNonlin's Model #4 lead to instable estimates of k01
and k10 (i.e., values are close together and show high
variances), the model may be over-parametrized; in such
a case you may opt for Model #5.
IMHO there is no direct connection which rich or sparse sampling.
<>
best regards,
Helmut Sch=FCtz
--
Helmut Sch=FCtz
BEBAC
Consultancy Services for Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna/Austria
tel/fax +43 1 2311746
Web http://BEBAC.at
BE/BA Forum http://forum.bebac.at
Back to the Top
The following message was posted to: PharmPK
Dear Helmut,
Thanks for your reply. I have one further question:
What is then the meaning of K in this model? Is it a hybrid of K01
and K10? Can it be used in dosing calculations?
Regards
Ronette
Ronette Gehring BVSc, MMedVet (Pharm)
Diplomate of the American College of Veterinary Clinical Pharmacology
Assistant Professor
Department of Clinical Sciences (Agricultural Practices)
Kansas State University, College of Veterinary Medicine
I 107 Mosier Hall
Manhattan
KS 66506
Back to the Top
The following message was posted to: PharmPK
Dear Ronette!
>you wrote:
>What is then the meaning of K in this model? Is it a hybrid of K01
>and K10? Can it be used in dosing calculations?
>
<>As already said, you should apply WinNonlin's Model #5 only,
if you are running into problems with Model #4.
Problems arise from parameter indentifiability.
If the 'true' values k01 and k10 are close together, the
SSQ-surface may become 'flat', making it very difficult for
the minimization-algorithm to find the 'true' minimum.
It's also possible that two local minima exists (instead of
one global).
In such a case the final estimates are very sensitive to the
given side conditions (initial parameter values, model bounds,
estimates, convergence criteria, number of maximal iterations,
mimimization algorithm,...); you may notice 'instable'
estimates (values of k01 and k10 close together and highly
correlated, high variance).
In such a case you may opt for Model #5, which is a
'borderline' situation of a 'flip-flop' model.
In a 'flip-flop' model the apparent elimination is actually
the absorption phase (which is slower than the 'true'
elimination). Without i.v. data it's not possible to
distinguish between k01 and k10.
Maybe on of Harold Boxenbaum's article may help:
http://www.ualberta.ca/~csps/JPPS1(3)/H.Boxenbaum/flip-boxenbaum.pdf
<>Model #5 simply sets k01=k10 yielding at stable solution, having
only two parameters (volume of distribution and k):
C(t)=k*(Dose/V)*t*exp(-k*t)
And yes, you may use the estimated k in dosing calculations,
although personally I would do so only, if all subjects
of a reasonably large data set shows a failure of Model #4.
best regards,
Helmut
--
Helmut Schuetz
BEBAC
Consultancy Services for Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna/Austria
tel/fax +43 1 2311746
Web http://BEBAC.at
BE/BA Forum http://forum.bebac.at
http://www.goldmark.org/netrants/no-word/attach.html
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)