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Re: higher AUC after bolus compared to infusion?

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

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