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metabolizes the drug or the functional capacity of metabolizing organs, e.g., the liver and kidney, are linearly related
to TBW. There is little evidence supporting this second
assumption because 99% of metabolic processes occur
within lean tissues.6 It is perhaps not too surprising then
that CL seems best linearly related to LBW rather than
TBW.7 The upshot in clinical practice is that subjects of
different body compositions should expect a similar drug
exposure if maintenance doses are determined on a milligram amount per kilogram of LBW. And here lies a
challenge: LBW has been prohibitively difficult to use in the
clinic, because accurate measurement via dual x-ray absorptiometry, for example, is not practical. Bioelectrical
impedance analysis (BIA) is more readily available as
demonstrated by Ingrande et al.,8 although more frequently, equations developed by James in 1976 are used to
estimate LBW.9 These equations cannot, however, be extrapolated to the obese because of numerical inconsistencies whereby LBW declines at certain weights and
heights.7,10 New semimechanistic LBW equations developed in 2005 are transportable to the obese, with readers
directed to the article by Janmahasatian et al.11 for a
complete derivation.
For propofol, there is clearly much confusion when
dosing the obese, with most prior work unable to help
anesthetists. The reason is that the obese have often been
excluded from studies, or James LBW equations have been
used to describe pharmacokinetic (PK) parameters. As
such, CL has been reported to increase linearly with TBW12
or vary with some form of James LBW13,14 (Fig. 1). The
empirical suggestion by Servin et al.15 of corrected
weight was a possible metric that might be applicable to
dosing the obese, although some have questioned its suitability in clinical practice.16,17 Trial design, subject population, and James LBW equations are responsible for the
variety of relationships between TBW and CL shown in
b
Even though he wasnt obese, did propofol contribute toward the death of
Michael Jackson?
From the *Model Answers Pty. Ltd., Brisbane; and School of Pharmacy, The
University of Queensland, Brisbane, Australia.
Accepted for publication October 3, 2010.
Conflict of Interest: See Disclosures at the end of the article.
Reprints will not be available from the authors.
Address correspondence to Bruce Green, DClinPharm, Director, Model
Answers, Suite 4, Level 18, 333 Ann St., Brisbane, Australia 4000. Address
e-mail to modelanswers@gmail.com.
Copyright 2011 International Anesthesia Research Society
DOI: 10.1213/ANE.0b013e318212eae8
This is somewhat of a simplification. CL determines the required maintenance dose of a drug when steady-state concentrations are reached. For
drugs that display single compartmental pharmacokinetics (PKs), steady
state is achieved immediately after the loading dose is administered. For
propofol and other drugs that display multicompartmental PKs, true steady
state might not be achieved during the course of dosing because of drug
transfer between compartments. The actual induction dose required to
achieve anesthesia may therefore depend on the rate of administration, rate
and extent of transfer to the peripheral compartments, and effect-site
hysteresis. Furthermore, for target-controlled infusion in effect-site targeting
mode, the doses are adjusted by the device to best achieve steady state
within the effect-site rather than in the central (i.e., plasma) compartment
(see Absalom et al.5 for more information). However, it is still central volume
of distribution and elimination CL that have the greatest influence on
required loading and maintenance doses, respectively, to achieve and
maintain pseudosteady-state/stable concentrations.
www.anesthesia-analgesia.org
EDITORIAL
models are transportable across a wide range of body compositions. More recent studies have attempted to do this,20,21
although some approaches cause confusion by failing to
consider the limitations of design on covariate selection.22 It is
therefore refreshing that Ingrande et al.8 are prospectively
assessing BIA for dosing propofol in the obese and exploring
a hypothesis based on mechanistic reasoning rather than
empiricism and tradition. They also note that LBW estimated
by the Janmahasatian et al. equation11 is a practical approach
in the clinic where BIA is unavailable.
In conclusion, we propose that it is time to move
forward and update PK models in TCI devices with ones
that are transportable to the obese. Lets stop making up
fudge factors for TCI devices and perhaps consider Janmahasatian et al.s LBW as a metric to dose propofol across a
population that includes the obese.
DISCLOSURES
www.anesthesia-analgesia.org
19. Liem EB, Lin CM, Suleman MI, Doufas AG, Gregg RG,
Veauthier JM, Loyd G, Sessler DI. Anesthetic requirement is
increased in redheads. Anesthesiology 2004;101:279 83
20. McLeay SC, Morrish GA, Kirkpatrick CM, Green B. Encouraging the move towards predictive population models for the
obese using propofol as a motivating example. Pharm Res
2009;26:1626 34
21. Cortinez LI, Anderson BJ, Penna A, Olivares L, Muoz HR,
Holford NH, Struys MM, Sepulveda P. Influence of obesity on
propofol pharmacokinetics: derivation of a pharmacokinetic
model. Br J Anaesth 2010;105:448 56
22. Han PY, Kirkpatrick CM, Green B. Informative study designs
to identify true parameter-covariate relationships. J Pharmacokinet Pharmacodyn 2009;36:147 63
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