# RE: Dilemma with PPK parameters

From: Ulrika Simonsson <ulrika.simonsson>
Date: Fri, 5 Feb 2010 19:06:40 +0100

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

From: owner-nmusers
On Behalf Of Serge Guzy
Sent: den 5 februari 2010 18:17
To: varsham
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: owner-nmusers
To: nmusers
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
varsham

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Received on Fri Feb 05 2010 - 13:06:40 EST

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