Back to the Top
The following message was posted to: PharmPK
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
E-mail: nele.plock.aaa.bayerhealthcare.com
Web: http://www.bayerscheringpharma.de
Back to the Top
Dear,
This can most likely be described by a model of non-instantaneous and
potentially irreversible binding kinetics to the intracellular
proteins/structures.
With bolus, you see the drug in plasma (hence higher AUC) before it
binds to the internal proteins irreversably.
With infusions, more of the drug has time to bind irreversably to the
internal structures, which is a tissue clearance (higher apparent
clearance with infusions leading to lower AUC).
At higher doses, you may saturate the proteins/internal structures and
you no longer have that tissue clearance. And after a certain dose
level, you will likely see more linear kinetics.
I've done some research on that some time ago (modeled the non-
instantaneous kinetics and measured them experimentally, then
simulated a clinical profile where these non-instantaneous kinetics of
protein binding played a role in the kinetics of the drug), a small
part of the work was published but the remainder has not been
published yet (I'm about 7 years late on writing that paper).
Malaz A AbuTarif, Ph.D., M.B.A.
Schering-Plough
Kenilworth, NJ
Back to the Top
The following message was posted to: PharmPK
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
Back to the Top
Hello,
This description sounds like Michaelis-Menten (MM) kinetics.
According to Wager the plasma clearance of the drug will change with
dose, and the plasma clearance of the drug would be expected to be
different following administration of the same dose in a rapidly
available and a slowly available dosage form [1].
To detect MM kinetics look for the signature "hockey-stick" curve:
The signature pattern form MM kinetics is a pseudolinear phase
gradually curving at lower concentrations to form the distinctive
"hockey-stick" shape of a descending linear IV plot [2].
MM kinetics can be implemented in NONMEM using ADVAN10.
Hope this is useful,
Mahesh
References.
[1] Wagner. Properties of the Michaelis-Menten equation and its
integrated form which are useful in pharmacokinetics. Journal of
Pharmacokinetics and Pharmacodynamics. 1: 103-21 (1973).
[2] Gentry. Determinants and Analysis of Blood Alcohol Concentrations
After Social Drinking. Alcoholism. Clinical and Experimental Research.
24: 399-399 (2000).
Back to the Top
The following message was posted to: PharmPK
This difference is probably due to nonlinear PK. Refer to any previous
IV bolus data of a different dose for this compound (if you have
them). By comparing the exposures, then the nonlin PK might become
evident. Also if you have oral data at different doses and if the
exposures are supraproportional then that would also explain it (use
caution when comparing the oral data as you might factoring in other
processes).
Neil
Back to the Top
The following message was posted to: PharmPK
Hi Nele,
As others have pointed out, this could be attributed to nonlinear
elimination. If a larger amount of the drug is introduced to the system
in a short time(iv bolus dose), you may saturate the elimination while
same amounts over a longer time period results in lower concentrations
and hence less or no saturation. One way to check this is to look at
drug concentrations at a lower dose iv dose. How does the curve look
like if you administered 1/5th of the iv dose you have tested? If there
is nonlinearity going on, your lower dose AUCs will be disproportionally
smaller than the higher iv dose.
Toufigh
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Higher AUC after bolus compared to infusion" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)