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RE: Dilemma with PPK parameters

From: Ken Kowalski <ken.kowalski>
Date: Fri, 5 Feb 2010 09:56:11 -0500

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
ken.kowalski



-----Original Message-----
From: owner-nmusers
Behalf Of Varsha Mehta
Sent: Friday, February 05, 2010 8:58 AM
To: nmusers
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
varsham

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Received on Fri Feb 05 2010 - 09:56:11 EST

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