Dear Group:
I am seeking some help to logically explain the difference in CL of a drug
between 2 groups who received the same drug for the same indication but one
group had induced hypothermia (treatment-N=24) while the other did not
(control-N=115).
The half life for control- 111hrs and treatment 129 hrs (roughly)- not
statistically different.
However, the parameters:
Control Group Treatment group
CL- 0.000105 L/kg/hr (suspect) CL- 0.00467 L/kg/hr
Vd -0.733 L/kg Vd 0.876 L/Kg
I used the same model for both groups and the half life calc was part of the
model. I have run the model for both multiple times using various theta values.
each time the minimization is complete. The bootstrap for treatment group gives
reasonably good agreement. The bootstrap for control parameters match well
for Cl (0.000273 L/kg/hr) but not for Vd (0.416 L/kg).
Given the relationship between Vd and CL how is this possible? How can the
half life be so close when there is such a huge difference in CL for both
groups? Where am I going wrong?
Would appreciate any help anyone can provide.
Thanks!!
Varsha Mehta, MS(CRDSA), Pharm.D., FCCP
Clinical Associate Professor
Pharmacy, Pediatrics and Communicable Diseases
Clinical Pharmacist Neonatal Critical Care
University of Michigan
(O) 734-936-8985
(F) 734-936-6946
[email protected]
**********************************************************
Electronic Mail is not secure, may not be read every day, and should not be
used for urgent or sensitive issues
pnc203.ctl
Description:
Binary data
Dilemma with PPK parameters
Hi Varsha,
In your control stream you have CL and Vd parameterized as:
TVCL = THETA(1) + THETA (3) * WT
TVVD = THETA(2) + THETA (4) * WT
Thus, THETA(1) and THETA(2) are the typical individual values of CL and Vd
at WT=0 which are meaningless parameters. If both CL and Vd are directly
proportional to WT then we would expect estimates of THETA(1) and THETA(2)
to go to zero. I don't know how this control stream relates to the
estimates you provide below because you don't have a covariate for treatment
group on CL or Vd but I assume you are reporting estimates for THETA(3) and
THETA(4). However, if your estimates of THETA(1) and THETA(2) are
substantially different from zero between groups then this may be the
explanation.
If you use the following parameterization:
TVCL = THETA(1) * WT
TVVD = THETA(2) * WT
I don't think you would see a disconnect. Of course, Nick would want you to
use WT**0.75 for CL.
Ken
Kenneth G. Kowalski
President & CEO
A2PG - Ann Arbor Pharmacometrics Group, Inc.
110 E. Miller Ave., Garden Suite
Ann Arbor, MI 48104
Work: 734-274-8255
Cell: 248-207-5082
Fax: 734-913-0230
[email protected]
Quoted reply history
-----Original Message-----
From: [email protected] [mailto:[email protected]] On
Behalf Of Varsha Mehta
Sent: Friday, February 05, 2010 8:58 AM
To: [email protected]
Subject: [NMusers] Dilemma with PPK parameters
Dear Group:
I am seeking some help to logically explain the difference in CL of a drug
between 2 groups who received the same drug for the same indication but one
group had induced hypothermia (treatment-N=24) while the other did not
(control-N=115).
The half life for control- 111hrs and treatment 129 hrs (roughly)- not
statistically different.
However, the parameters:
Control Group Treatment group
CL- 0.000105 L/kg/hr (suspect) CL- 0.00467 L/kg/hr
Vd -0.733 L/kg Vd 0.876 L/Kg
I used the same model for both groups and the half life calc was part of the
model. I have run the model for both multiple times using various theta
values. each time the minimization is complete. The bootstrap for treatment
group gives reasonably good agreement. The bootstrap for control parameters
match well for Cl (0.000273 L/kg/hr) but not for Vd (0.416 L/kg).
Given the relationship between Vd and CL how is this possible? How can the
half life be so close when there is such a huge difference in CL for both
groups? Where am I going wrong?
Would appreciate any help anyone can provide.
Thanks!!
Varsha Mehta, MS(CRDSA), Pharm.D., FCCP
Clinical Associate Professor
Pharmacy, Pediatrics and Communicable Diseases Clinical Pharmacist Neonatal
Critical Care University of Michigan
(O) 734-936-8985
(F) 734-936-6946
[email protected]
**********************************************************
Electronic Mail is not secure, may not be read every day, and should not be
used for urgent or sensitive issues
Dear Varsha,
Did you evaluate the clearances as a continuous variable with changing
temperature. I suspect that the hypothermia induced was not constant over the
entire period so there may be a temperature dependent effect over the slices of
time observed with this information. I have taken the liberty of copying
Professor Poloyac at the University of Pittsburgh. This group has been
extensively involved in evaluating hypothermia effects on clearance.
Best Regards,
Rob
Robert R. Bies Pharm.D.Ph.D.
Associate Professor of Medicine and Medical Genetics
Division of Clinical Pharmacology
Member
Center for Computational Biology and Bioinformatics
Indiana University School of Medicine
1001 W 10th Street W7138
Indianapolis, IN 46202
317-630-7868 (office)
317-630-8185 (fax)
Quoted reply history
-----Original Message-----
From: [email protected] [mailto:[email protected]] On
Behalf Of Varsha Mehta
Sent: Friday, February 05, 2010 8:58 AM
To: [email protected]
Subject: [NMusers] Dilemma with PPK parameters
Dear Group:
I am seeking some help to logically explain the difference in CL of a drug
between 2 groups who received the same drug for the same indication but one
group had induced hypothermia (treatment-N=24) while the other did not
(control-N=115).
The half life for control- 111hrs and treatment 129 hrs (roughly)- not
statistically different.
However, the parameters:
Control Group Treatment group
CL- 0.000105 L/kg/hr (suspect) CL- 0.00467 L/kg/hr
Vd -0.733 L/kg Vd 0.876 L/Kg
I used the same model for both groups and the half life calc was part of the
model. I have run the model for both multiple times using various theta values.
each time the minimization is complete. The bootstrap for treatment group gives
reasonably good agreement. The bootstrap for control parameters match well
for Cl (0.000273 L/kg/hr) but not for Vd (0.416 L/kg).
Given the relationship between Vd and CL how is this possible? How can the
half life be so close when there is such a huge difference in CL for both
groups? Where am I going wrong?
Would appreciate any help anyone can provide.
Thanks!!
Varsha Mehta, MS(CRDSA), Pharm.D., FCCP
Clinical Associate Professor
Pharmacy, Pediatrics and Communicable Diseases Clinical Pharmacist Neonatal
Critical Care University of Michigan
(O) 734-936-8985
(F) 734-936-6946
[email protected]
**********************************************************
Electronic Mail is not secure, may not be read every day, and should not be
used for urgent or sensitive issues
I did not see the data but could you envisage that you have may be model
misspecification. Half life relationship to clearance applies for example to
the one compartmental model assumption. What if you have multiple half lives? I
would not expect a simple relationship between a model using one half life with
clearance when the true model has multiple one.
As far as I know the non compartmental relationship applies to clerance with
volume and elimination rate and assumes linear kinetics.
Best
Serge guzy,PhD
President,CEO,POPPHARM
Quoted reply history
----- Original Message -----
From: [email protected] <[email protected]>
To: [email protected] <[email protected]>
Sent: Fri Feb 05 05:58:01 2010
Subject: [NMusers] Dilemma with PPK parameters
Dear Group:
I am seeking some help to logically explain the difference in CL of a drug
between 2 groups who received the same drug for the same indication but one
group had induced hypothermia (treatment-N=24) while the other did not
(control-N=115).
The half life for control- 111hrs and treatment 129 hrs (roughly)- not
statistically different.
However, the parameters:
Control Group Treatment group
CL- 0.000105 L/kg/hr (suspect) CL- 0.00467 L/kg/hr
Vd -0.733 L/kg Vd 0.876 L/Kg
I used the same model for both groups and the half life calc was part of the
model. I have run the model for both multiple times using various theta values.
each time the minimization is complete. The bootstrap for treatment group gives
reasonably good agreement. The bootstrap for control parameters match well
for Cl (0.000273 L/kg/hr) but not for Vd (0.416 L/kg).
Given the relationship between Vd and CL how is this possible? How can the
half life be so close when there is such a huge difference in CL for both
groups? Where am I going wrong?
Would appreciate any help anyone can provide.
Thanks!!
Varsha Mehta, MS(CRDSA), Pharm.D., FCCP
Clinical Associate Professor
Pharmacy, Pediatrics and Communicable Diseases
Clinical Pharmacist Neonatal Critical Care
University of Michigan
(O) 734-936-8985
(F) 734-936-6946
[email protected]
**********************************************************
Electronic Mail is not secure, may not be read every day, and should not be
used for urgent or sensitive issues
--
The information contained in this email message may
contain confidential or legally privileged information and is intended solely
for the use of the named recipient(s). No confidentiality or privilege is
waived or lost by any transmission error. If the reader of this message is
not the intended recipient, please immediately delete the e-mail and all
copies of it from your system, destroy any hard copies of it and notify the
sender either by telephone or return e-mail. Any direct or indirect use,
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prohibited. Any views expressed in this message are those of the individual
sender, except where the message states otherwise and the sender is
authorized to state them to be the views of XOMA.
Dear all,
Just a short note:
There is still a relationship between CL and half-lives for a two-compartmental
model although not as simple as for a one compartmental model.
For a two-compartmental model you can derive the two half-lives (t1/2alpha and
t1/2 beta) through either estimates of macro (CL, V2, V3, Q) or micro constants
(K10,K21,K12) through (2 comp iv model):
K10=CL/V1
K12=Q/V1
K21=Q/V2
SUM=K10+K12+K21
ROOT=SQRT(SUM*SUM-4*K21*K10)
Alpha=0.5*(SUM+ROOT)
Beta=0.5*(SUM-ROOT)
t1/2alpha=LN(2)/Alpha
t1/2beta=LN(2)/Beta
Best regards,
Ulrika
Ulrika Simonsson, PhD
Assoc Prof of Pharmacometrics
Uppsala Pharmacometrics
Department of Pharmaceutical Biosciences
Uppsala University
BMC, Box 591, 751 24 Uppsala
Sweden
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Serge Guzy
Sent: den 5 februari 2010 18:17
To: [email protected]; [email protected]
Subject: Re: [NMusers] Dilemma with PPK parameters
I did not see the data but could you envisage that you have may be model
misspecification. Half life relationship to clearance applies for example to
the one compartmental model assumption. What if you have multiple half lives? I
would not expect a simple relationship between a model using one half life with
clearance when the true model has multiple one.
As far as I know the non compartmental relationship applies to clerance with
volume and elimination rate and assumes linear kinetics.
Best
Serge guzy,PhD
President,CEO,POPPHARM
----- Original Message -----
From: [email protected] <[email protected]>
To: [email protected] <[email protected]>
Sent: Fri Feb 05 05:58:01 2010
Subject: [NMusers] Dilemma with PPK parameters
Dear Group:
I am seeking some help to logically explain the difference in CL of a drug
between 2 groups who received the same drug for the same indication but one
group had induced hypothermia (treatment-N=24) while the other did not
(control-N=115).
The half life for control- 111hrs and treatment 129 hrs (roughly)- not
statistically different.
However, the parameters:
Control Group Treatment group
CL- 0.000105 L/kg/hr (suspect) CL- 0.00467 L/kg/hr
Vd -0.733 L/kg Vd 0.876 L/Kg
I used the same model for both groups and the half life calc was part of the
model. I have run the model for both multiple times using various theta values.
each time the minimization is complete. The bootstrap for treatment group gives
reasonably good agreement. The bootstrap for control parameters match well
for Cl (0.000273 L/kg/hr) but not for Vd (0.416 L/kg).
Given the relationship between Vd and CL how is this possible? How can the
half life be so close when there is such a huge difference in CL for both
groups? Where am I going wrong?
Would appreciate any help anyone can provide.
Thanks!!
Varsha Mehta, MS(CRDSA), Pharm.D., FCCP
Clinical Associate Professor
Pharmacy, Pediatrics and Communicable Diseases
Clinical Pharmacist Neonatal Critical Care
University of Michigan
(O) 734-936-8985
(F) 734-936-6946
[email protected]
**********************************************************
Electronic Mail is not secure, may not be read every day, and should not be
used for urgent or sensitive issues
_____
The information contained in this email message may contain confidential or
legally privileged information and is intended solely for the use of the named
recipient(s). No confidentiality or privilege is waived or lost by any
transmission error. If the reader of this message is not the intended
recipient, please immediately delete the e-mail and all copies of it from your
system, destroy any hard copies of it and notify the sender either by telephone
or return e-mail. Any direct or indirect use, disclosure, distribution,
printing, or copying of any part of this message is prohibited. Any views
expressed in this message are those of the individual sender, except where the
message states otherwise and the sender is authorized to state them to be the
views of XOMA.
Hi Varsha,
Continuing on Ken's response, have you tried a simple model without any
covariates? Do you get the same values
for CL as you do with the control stream you provided? Could you also provide
the
values for all the four THETAs you estimate in your control stream?
Toufigh
On Fri 02/05/10 8:58 AM , "Varsha Mehta" [email protected] sent:
> Dear Group:
> I am seeking some help to logically explain the difference in CL of
> a drug between 2 groups who received the same drug for the same
> indication but one group had induced hypothermia (treatment-N=24)
> while the other did not (control-N=115).
> The half life for control- 111hrs and treatment 129 hrs (roughly)-
> not statistically different.
> However, the parameters:
> Control Group Treatment group
> CL- 0.000105 L/kg/hr (suspect) CL- 0.00467 L/kg/hr
> Vd -0.733 L/kg Vd 0.876 L/Kg
>
> I used the same model for both groups and the half life calc was
> part of the model. I have run the model for both multiple times using
> various theta values. each time the minimization is complete. The
> bootstrap for treatment group gives reasonably good agreement. The
> bootstrap for control parameters match well for Cl (0.000273
> L/kg/hr) but not for Vd (0.416 L/kg).
> Given the relationship between Vd and CL how is this possible? How
> can the half life be so close when there is such a huge difference in
> CL for both groups? Where am I going wrong?
> Would appreciate any help anyone can provide.
> Thanks!!
> Varsha Mehta, MS(CRDSA), Pharm.D., FCCP
> Clinical Associate Professor
> Pharmacy, Pediatrics and Communicable Diseases
> Clinical Pharmacist Neonatal Critical Care
> University of Michigan
> (O) 734-936-8985
> (F) 734-936-6946
> **********************************************************
> Electronic Mail is not secure, may not be read every day, and should
> not be used for urgent or sensitive issues
>
>
Dear all and dear Varsha,
There are so many problem posed to this list that could be sensibly answered
if a control file had been attached. This is probably one of them. Please
provide model files if you are asking questions about why your model doesn't
work (sometimes also a small portion of the data set is needed). The list
has many contributors that are eager to help, why not giving them an honest
chance of doing so. Providing model files could also be instructive to
others, I often learn new coding possibilities and clever ways of doing
things by reading code from others.
Finally, it is always appreciated to learn if and how the problem was
solved.
Best regards,
Mats
Mats Karlsson, PhD
Professor of Pharmacometrics
Dept of Pharmaceutical Biosciences
Uppsala University
Box 591
751 24 Uppsala Sweden
phone: +46 18 4714105
fax: +46 18 471 4003
Quoted reply history
-----Original Message-----
From: [email protected] [mailto:[email protected]] On
Behalf Of Varsha Mehta
Sent: Friday, February 05, 2010 2:58 PM
To: [email protected]
Subject: [NMusers] Dilemma with PPK parameters
Dear Group:
I am seeking some help to logically explain the difference in CL of a drug
between 2 groups who received the same drug for the same indication but one
group had induced hypothermia (treatment-N=24) while the other did not
(control-N=115).
The half life for control- 111hrs and treatment 129 hrs (roughly)- not
statistically different.
However, the parameters:
Control Group Treatment group
CL- 0.000105 L/kg/hr (suspect) CL- 0.00467 L/kg/hr
Vd -0.733 L/kg Vd 0.876 L/Kg
I used the same model for both groups and the half life calc was part of the
model. I have run the model for both multiple times using various theta
values. each time the minimization is complete. The bootstrap for treatment
group gives reasonably good agreement. The bootstrap for control parameters
match well for Cl (0.000273 L/kg/hr) but not for Vd (0.416 L/kg).
Given the relationship between Vd and CL how is this possible? How can the
half life be so close when there is such a huge difference in CL for both
groups? Where am I going wrong?
Would appreciate any help anyone can provide.
Thanks!!
Varsha Mehta, MS(CRDSA), Pharm.D., FCCP
Clinical Associate Professor
Pharmacy, Pediatrics and Communicable Diseases Clinical Pharmacist Neonatal
Critical Care University of Michigan
(O) 734-936-8985
(F) 734-936-6946
[email protected]
**********************************************************
Electronic Mail is not secure, may not be read every day, and should not be
used for urgent or sensitive issues