From: Leonid Gibiansky <*lgibiansky*>

Date: Fri, 22 Nov 2013 13:43:32 -0500

Nele,

I am not sure why would you like to divide by F1.

Can we just do it explicitly?

F1=EXP(ETA(1))

(or F1=function(dose)*EXP(ETA(1))

CL=..

V=..

F1 can be > 1 as it is not absolute but relative (to the other

subjects); I assume that this is oral dose, not IV, correct?

In your code, be careful not to call it F1 as the nonmem will interpret

it as bioavailability parameter, and you should not account for it twice.

So it should be either

F1=EXP(ETA(1))

CL=THETA()*EXP(ETA())

V=THETA()*EXP(ETA())

or

F1=1 (can me implicit and omitted)

FF1=EXP(ETA(1))

CL=THETA()*EXP(ETA())/FF1

V=THETA()*EXP(ETA())/FF1

but not

F1=EXP(ETA(1))

CL=THETA()*EXP(ETA())/F1

V=THETA()*EXP(ETA())/F1

Leonid

--------------------------------------

Leonid Gibiansky, Ph.D.

President, QuantPharm LLC

web: www.quantpharm.com

e-mail: LGibiansky at quantpharm.com

tel: (301) 767 5566

On 11/22/2013 12:14 PM, Mueller-Plock, Nele wrote:

*> Dear all,
*

*>
*

*> I have come across an interesting proposal to account for correlation between CL and volume parameters by dividing by bioavailability within the NONMEM control stream:
*

*>
*

*> http://www.wright-dose.com/tip2.php
*

*>
*

*> I liked the approach, however I have been wondering how exactly to interpret the resulting parameter values for CL and V.
*

*>
*

*> As an illustration, a potential problem might be that we have doses of 10, 25 and 50 mg with a fixed bioavailability of 100% for the 10 mg dose, and bioavailabilities of 80% and 50% for the doses of 25 and 50 mg, respectively. In addition, a between-subject variability on F1 of ~30% would be present.
*

*>
*

*> If I now code my CL and V as follows:
*

*> CL=THETA(1)/F1
*

*> V=THETA(2)/F1,
*

*> to account for the correlation between CL and V, what exactly would be the meaning/interpretation of THETA(1) and THETA(2)?
*

*> As the THETAs would be the same for all doses, the CL of 50 mg would be twice as high as the one for the 10 mg dose – does that make sense, as we already estimated the reduced relative bioavailability using parameter F1?
*

*>
*

*> Any comments would be very much appreciated.
*

*> Thanks and best
*

*> Nele
*

*>
*

*>
*

*>
*

*> Dr. Nele Müller-Plock, CAPM
*

*> Principal Scientist Modeling and Simulation
*

*> Pharmacometrics
*

*> Experimental Medicine
*

*>
*

*> Takeda Pharmaceuticals International GmbH
*

*> 8152 Glattpark-Opfikon (Zürich)
*

*> Switzerland
*

*>
*

*> Visitor address:
*

*> Alpenstrasse 3
*

*> 8152 Glattpark-Opfikon (Zürich)
*

*> Switzerland
*

*>
*

*> Phone: (+41) 44 / 55 51 404
*

*> Mobile: (+41) 79 / 654 33 99
*

*> mailto: nele.mueller-plock *

*> http://www.takeda.com
*

*> --------------------------------------------------------------------
*

*>
*

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Received on Fri Nov 22 2013 - 13:43:32 EST

Date: Fri, 22 Nov 2013 13:43:32 -0500

Nele,

I am not sure why would you like to divide by F1.

Can we just do it explicitly?

F1=EXP(ETA(1))

(or F1=function(dose)*EXP(ETA(1))

CL=..

V=..

F1 can be > 1 as it is not absolute but relative (to the other

subjects); I assume that this is oral dose, not IV, correct?

In your code, be careful not to call it F1 as the nonmem will interpret

it as bioavailability parameter, and you should not account for it twice.

So it should be either

F1=EXP(ETA(1))

CL=THETA()*EXP(ETA())

V=THETA()*EXP(ETA())

or

F1=1 (can me implicit and omitted)

FF1=EXP(ETA(1))

CL=THETA()*EXP(ETA())/FF1

V=THETA()*EXP(ETA())/FF1

but not

F1=EXP(ETA(1))

CL=THETA()*EXP(ETA())/F1

V=THETA()*EXP(ETA())/F1

Leonid

--------------------------------------

Leonid Gibiansky, Ph.D.

President, QuantPharm LLC

web: www.quantpharm.com

e-mail: LGibiansky at quantpharm.com

tel: (301) 767 5566

On 11/22/2013 12:14 PM, Mueller-Plock, Nele wrote:

Received on Fri Nov 22 2013 - 13:43:32 EST