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

**********************************************************

Electronic Mail is not secure, may not be read every day, and should not be

used for urgent or sensitive issues

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

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

**********************************************************

Electronic Mail is not secure, may not be read every day, and should not be

used for urgent or sensitive issues

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