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Dear All,
I wonder if somebody can help me interpret some population modelling
results. We have fit a 1 compartment model to midazolam plasma data
following continuous infusion in neonates treated using
extracorporeal membrane oxygenation (ECMO). For those of you who have
never come across ECMO, it is a prolonged form of cardiopulmonary
(CPB) bypass, i.e. whereas CPB lasts for 2-3 hours, ECMO may continue
for days or even weeks. The technique involves draining venous blood
out from the right side of the heart, oxygenating it outside the body
using artificial (silicone membrane) oxygenators, and returning it
back into the venous or arterial circulation, thereby allowing the
diseased native lung/heart to rest and recover. This is akin to
dialysis, but the volume of blood drained, the flow rate and the size
of the circuit is much larger in ECMO.
We have determined that there is a time dependent change in the PK,
so that in the first 12 hours there is a significantly higher
clearance and volume, but thereafter clearance significantly reduces
and volume of distribution greatly increases. I would have expected a
lower clearance and higher volume of distribution initally (beacause
of the expanded circulating volume, and adsorption of the drug to the
PVC circuit- the latter has been shown in vitro and ex-vivo studies),
but then as the circuit reaches saturation point for the Volume of
distribution to contract and clearance to increase. Can anyone
explain?
Could it be related to protein binding, since albumin levels
initially on ECMO are lower due to haemodilution as the patient is
placed onto ECMO, but are then corrected fairly rapidly (Midazolam is
95% bound).
Any comment greatly appreciated.
Sincerely
Hussain Mulla
Research Associate
Department of Pharmacy
Glenfield Hospital
Leicester
England
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The following message was posted to: PharmPK
Re: Midazolam modeling
>Could it be related to protein binding, since albumin levels
>initially on ECMO are lower due to haemodilution as the patient is
>placed onto ECMO, but are then corrected fairly rapidly (Midazolam
>is 95% bound).
>
Yes, it could very well be. Midazolam is metabolized by 3A4 in both
gut and liver. Your doses are IV, so gut metabolism will be minimal -
limited to partitioning of unbound drug into the enterocytes from the
basolateral side.
We don't have data on neonates, but a quick simulation for midazolam
in adults using a saturable metabolism model with 2-compartment
pharmacokinetics fitted from IV data shows that simply increasing the
unbound fraction in plasma from 4% to 8% for a 15 mg oral dose
results in a drop in Cmax from about 50 ng/mL to about 30 ng/mL and
in AUC from about 145 ng-h/mL down to about 70 ng-h/mL - using the
same central compartment volume of about 0.7 L/kg, K12 = 0.227/h, and
K21 = 0.59/h.
Fitting a 1-compartment model with fixed clearance to accommodate
these changes would lead to an apparent change in volume and
clearance, when it may be protein binding combined with saturable
metabolism. Neonates may be different in other ways, but your guess
of plasma protein binding changes causing the apparent shift in
1-compartment PK parameters seems plausible.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
E-mail: walt.at.simulations-plus.com
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Few factors come to my mind from experiments with CPB. These are
body temperature, haemodilution, protein adsorption to the ECMO unit
and altered perfusion.
Have you lowered the temperature of the body? A small change (1-2
degree C) may decrease the clearance of the drug due to several
factors (e.g. enzyme activity, transport, etc).
The ECMO may have altered the perfusion of the clearing organs.
Haemodilution will decrease plasma protein concentration and decrease
binding. Lipophilic drugs and binding proteins are adsorbed to the
units of CPB specially the oxygenator membrane. We did some
preliminary study (Pharm Res 10(10):299, 1993) that showed that
plasma proteins such as alpha-1 acid glycoprotein may get adsorbed to
the membrane. I have not checked if there is any study to show that
some plasma proteins may get denatured during the process. These
factors may have contribute to the increased volume of distribution
throughout the study.
(NB: is there any plasticizer coming out from the unit?)
I hope this helps,
Delwar
Delwar Hussain, Ph.D.
Atrix laboratories
Fort Collins, CO 80525
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I don't know the major site(s) of Midazolam metabolism, but there is
evidence of significant decreases in cerebral and renal blood flow
with initiation of venoarterial ECMO. The decrease is mediated by
local increases in vascular resistance, so there is a real
possibility that changes in perfusion of the metabolizing organ(s)
occurs.
Arlin Blood
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