From: saik.urien.svp <*saik.urien*>

Date: Thu, 04 Dec 2008 15:32:20 +0100

Nele

It is possible to simulate

AUC_iv_bolus = 3*AUC_3h_inf

This was done using the code below, assuming a saturation in both

elimination and distribution in the peripheral compartment (similar to the

pharmacokinetics of taxol)

The problem is that the AUC_0.5h_inf is intermediate and closer to the

bolus AUC than to the 3h_inf AUC value

A model with auto-induction could also increase the AUC_iv_bolus with an

intermediate value for the 0.5h infusion AUC

Hoping that this helps

Regards

Saik

$MODEL COMP=(CP,DEFOBS,DEFDOSE) COMP=(PERI) COMP=(AUC)

$PK

VM=THETA(1)*EXP(ETA(1))

KM=THETA(2)*EXP(ETA(2))

V1=THETA(3)*EXP(ETA(3))

VM12=THETA(4)

KM12=THETA(5)

K21=THETA(6)

$DES

DADT(1)=-VM*A(1)/(A(1)+V1*KM)+K21*A(2)-VM12*A(1)/(A(1)+V1*KM12)

DADT(2)=-K21*A(2)+VM12*A(1)/(A(1)+V1*KM12)

DADT(3)= A(1)

$ERROR

Y=A(1)/V1*EXP(EPS(1))

AUC = A(3)

$THETA (0,20) ; VM

$THETA (0,1) ; KM

$THETA (0,1) ; V1

$THETA (0,5) ; VM12

$THETA (0,.5) ; KM12

$THETA (0,.1);k21

----- Original Message -----

From: <nele.plock

To: <nmusers

Sent: Thursday, December 04, 2008 10:02 AM

Subject: [NMusers] higher AUC after bolus compared to infusion?

Dear all,

I have trouble modeling some rat PK data obtained after intravenous

dosing. I have dense data for two different doses, given either as bolus,

half-hour or 3-hour infusion. We know that the compound has a large

binding affinity to intracellular structures and therefore has a high

volume of distribution (~100L/kg in rats). However, what we observed in

the mentioned study is that the AUC after bolus dosing is ~3 times higher

than after infusions (no difference between 0.5 and 3 h), and this was

observed for both dose groups (effect a bit less pronounced for high dose,

but still there). Noncompartmental analysis indicates that this is due to

lower clearance and not a change in Vss. At the moment I have no idea what

kind of model would capture an observation like this. Has anybody ever

observed something like this, and even better, have some ideas on model

coding? Any ideas would be welcome!

Best regards

Nele

_________________________________________

Bayer Schering Pharma AG

Development Pharmacokinetics

Berlin, S109, 03, 306A

Phone: +49 30 468-15146

Fax: +49 30 468-11527

E-mail: nele.plock

Web: http://www.bayerscheringpharma.de

Vorstand: Andreas Fibig, Vorsitzender | Werner Baumann, Andreas Busch,

Ulrich Köstlin, Kemal Malik, Bernd Metzner, Gunnar Riemann

Vorsitzender des Aufsichtsrats: Werner Wenning

Sitz der Gesellschaft: Berlin | Eintragung: Amtsgericht Charlottenburg HRB

283 B

Received on Thu Dec 04 2008 - 09:32:20 EST

Date: Thu, 04 Dec 2008 15:32:20 +0100

Nele

It is possible to simulate

AUC_iv_bolus = 3*AUC_3h_inf

This was done using the code below, assuming a saturation in both

elimination and distribution in the peripheral compartment (similar to the

pharmacokinetics of taxol)

The problem is that the AUC_0.5h_inf is intermediate and closer to the

bolus AUC than to the 3h_inf AUC value

A model with auto-induction could also increase the AUC_iv_bolus with an

intermediate value for the 0.5h infusion AUC

Hoping that this helps

Regards

Saik

$MODEL COMP=(CP,DEFOBS,DEFDOSE) COMP=(PERI) COMP=(AUC)

$PK

VM=THETA(1)*EXP(ETA(1))

KM=THETA(2)*EXP(ETA(2))

V1=THETA(3)*EXP(ETA(3))

VM12=THETA(4)

KM12=THETA(5)

K21=THETA(6)

$DES

DADT(1)=-VM*A(1)/(A(1)+V1*KM)+K21*A(2)-VM12*A(1)/(A(1)+V1*KM12)

DADT(2)=-K21*A(2)+VM12*A(1)/(A(1)+V1*KM12)

DADT(3)= A(1)

$ERROR

Y=A(1)/V1*EXP(EPS(1))

AUC = A(3)

$THETA (0,20) ; VM

$THETA (0,1) ; KM

$THETA (0,1) ; V1

$THETA (0,5) ; VM12

$THETA (0,.5) ; KM12

$THETA (0,.1);k21

----- Original Message -----

From: <nele.plock

To: <nmusers

Sent: Thursday, December 04, 2008 10:02 AM

Subject: [NMusers] higher AUC after bolus compared to infusion?

Dear all,

I have trouble modeling some rat PK data obtained after intravenous

dosing. I have dense data for two different doses, given either as bolus,

half-hour or 3-hour infusion. We know that the compound has a large

binding affinity to intracellular structures and therefore has a high

volume of distribution (~100L/kg in rats). However, what we observed in

the mentioned study is that the AUC after bolus dosing is ~3 times higher

than after infusions (no difference between 0.5 and 3 h), and this was

observed for both dose groups (effect a bit less pronounced for high dose,

but still there). Noncompartmental analysis indicates that this is due to

lower clearance and not a change in Vss. At the moment I have no idea what

kind of model would capture an observation like this. Has anybody ever

observed something like this, and even better, have some ideas on model

coding? Any ideas would be welcome!

Best regards

Nele

_________________________________________

Bayer Schering Pharma AG

Development Pharmacokinetics

Berlin, S109, 03, 306A

Phone: +49 30 468-15146

Fax: +49 30 468-11527

E-mail: nele.plock

Web: http://www.bayerscheringpharma.de

Vorstand: Andreas Fibig, Vorsitzender | Werner Baumann, Andreas Busch,

Ulrich Köstlin, Kemal Malik, Bernd Metzner, Gunnar Riemann

Vorsitzender des Aufsichtsrats: Werner Wenning

Sitz der Gesellschaft: Berlin | Eintragung: Amtsgericht Charlottenburg HRB

283 B

Received on Thu Dec 04 2008 - 09:32:20 EST