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Dear Sirs
I need help from somebody,
Is there any or would be any pharmacokinetic difference between total body
weight and body surface area for the calculation of total daily dose of
aminoglycosides?, Usualy we use the total body weight, some authors had used
the body surface to calculate the aminoglycoside dose specialy in children.
I know that body surface calculation is influenced by weight.
Body weight in cancer patients will give some "false" interpretations, does
it?. Please advice or refere me to some references.Thank you.
N.Krivoy MD
Director of Clinical Pharmacology Unit
Rambam Medical Center, Haifa, Israel
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"Dr. N. Krivoy (by way of David_Bourne)" wrote:
> Is there any or would be any pharmacokinetic difference between total body
> weight and body surface area for the calculation of total daily dose of
> aminoglycosides?
Broadly speaking volume of distribution is proportional to weight and
clearance is proportional to weight to the power 3/4. Total daily dose
implies you are interested in the maintenance dose rate so clearance is
the relevant parameter.
Differences in predicted clearance based on the per kg, surface area or
3/4 power model are described in Holford NHG. A size standard for
pharmacokinetics. Clin. Pharmacokin. 1996: 30:329-332. In a nutshell the
surface area model is distinguishable from the 3/4 power model with
underprediction of dose extrapolated from adult values by more than 10%
when weights are less than 20 kg. The per kg model predicts doses that
are more than 10% too low when weights are less than 27 kg.
A measure of renal function is also an important independent determinant
of clearance apart from weight. If you use accurately measured
creatinine clearance then you can more or less ignore weight because
aminoglycoside clearance and creatinine clearance are highly correlated.
If you predict creatinine clearance using weight and serum creatinine
then this usually takes care of the body size issue. Even though weight
enters into the creatinine clearance prediction formula in a per kg
manner it is being used to predict a structural property of the body
(muscle mass and thus creatinine production rate) and so may be more
predictive than the 3/4 power model which relates to functional
properties.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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Dear All
I was interested to see the correspondence concerning use of body surface
area (BSA) or body weight for calculating gentamicin dosage.
BSA has been used widely in the calculation of dose for cytotoxic
anticancer drugs, but this dogma is being challenged increasingly. We are
presently studying a drug where the comparison of AUC (sorry to introduce
that contentious parameter again) to dose in mg/sq.m suggested
non-linearity, but this may well have been an artifact of adjusting for
body surface area as a comparison of AUC and absolute dose did not suggest
non-linearity.
Can I broaden the discussion and ask whether people feel the adoption of
body surface area dosing in oncology (or other disciplines) is appropriate,
or should we strive to change the "dogma" and only correct for body surface
area when it has been clearly shown to correlate with clearance.
Duncan Jodrell
***************************************************************
Duncan I. Jodrell DM, MSc, FRCP (Edin.),
Deputy Director, ICRF Medical Oncology Unit,
University of Edinburgh, Western General Hospital,
Edinburgh, EH4 2XU.
jodrell.-a-.icrf.icnet.uk
Tel: 0131 467 8447
Fax: 0131 332 8494
***************************************************************
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Reply-To: "Stephen Duffull"
From: "Stephen Duffull"
To:
Subject: Total BW or BSA for aminoglycoside
Date: Thu, 1 Jul 1999 09:03:04 +0100
MIME-Version: 1.0
X-Priority: 3
Hi Duncan
I think you have answered the question already (although I
would expand your mention of CL to include volume terms as
well).
Oncology and Haematology units tend to be *very* protocol
orientated. Their treatment plans tend to be based on
evidence based medicine. Unfortunately when the evidence is
based on inadequate trial design or inappropriate
assumptions (perhaps due to "dogma") then this does cast
considerable doubt on the clinical practice. In my opinion
we should be striving for the development of individual
dosing regimens for each drug/drug combination for the
treatment of each neoplastic condition in the population and
then determining how these regimens can be best
individualised for the patient. Therefore it seems that
there can be no place for dogma.
Regards
Steve
=====================
Stephen Duffull
School of Pharmacy
University of Manchester
Manchester, M13 9PL, UK
Ph +44 161 275 2355
Fax +44 161 275 2396
---
Date: Thu, 1 Jul 1999 01:28:18 -0700 (MST)
X-Sender: ml11439.-a-.pop.goodnet.com
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To: PharmPK.aaa.boomer.org
From: ml11439.-a-.goodnet.com (Michael J. Leibold)
Subject: Total BW or BSA for aminoglycoside
Dr.Krivoy,
Aminoglycoside doses are typically based on total body weight, unless
the patient is obese (>120% IBW). If the patient is obese, then dosing
body weight (DBW) is typically used, which is DBW=IBW +0.4(ABW-IBW). The
dosing body weight (DBW) takes into account the relatively poor distribution
of aminoglycosides into fat tissue.
So that for a 5mg/kg daily dose would be 5mg x Kg ABW unless the
the patient is obese, then 5mg/kg daily would be 5mg x Kg DBW.
Various empiric dosage schemes have been developed for children and
neonates which are generally based on total body weight. The following are
gentamicin/tobramycin dosing sehemes from Therapeutic Drug Monitoring, Gerald
Schumacher Editor:
Patient group Dosage regimen
Neonates
<28 weeks gestation 2.5mg/kg q24hrs
28-34 weeks gestation 2.5mg/kg q18hrs
>34 weeks gestation 2.5mg/kg q12hrs
Children 6-7.5mg/kg/24hrs
in 3 doses
Adults
Loading dose 1.75mg-2.0mg/kg
Maintenance dose 3-5.0mg/kg/24hrs
Dialysis
Loading dose 1.75-2.0mg/kg
Maintenance dose
Dialysis three times weekly 1-1.5mg/kg after dialysis
Dialysis daily 0.5-0.75mg/kg after dialysis
Cystic fibrosis
Children (3mth-17yrs) 3mg/kg q6hrs
Adult(>=18yrs) 3mg/kg q8hrs
Special populations considered in aminoglycoside dosing include age,
cystic fibrosis, congestive heart failure, liver disease, obesity, burns
and renal function.
Miscellaneous factors influencing aminoglycoside dosing include
hematological malignancy in which an elevated volume of distribution
and shorter half-life have been found in some studies, while others have
found no difference. This suggests dosage individualization with
pharmacokinetic dosing in this population to maintain the aminoglyoside
serum levels in the therapeutic range of 0.5-1.5ug/ml for troughs, and
5-8ug/ml for peaks.
References:
1) Schmacher, Gerald ed., Therapeutic Drug Monitoring, London, Appleton&
Lange 1995;p237-294
2) Evans, William E., Schentag, J.J., Jusko, W.J., Applied Pharmacokinetics
3rd edition,Vancouver, Applied Therapeutics 1992;p14-1 to 14-47
I hope this helps!!
Mike Leibold, PharmD, RPH
ML11439.-a-.goodnet.com
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"Duncan Jodrell (by way of David_Bourne)" wrote:
> BSA has been used widely in the calculation of dose for cytotoxic
> anticancer drugs, but this dogma is being challenged increasingly.
The "challenges" I have seen are mainly that dose individualization
using BSA or doing no individualization give much the same results in
terms of outcome. This is because the range of sizes in the study
populations is small in relation to the residual (after size correction)
between-subject variability. If adults and children were compared I don't
think there would be anyone who would seriously say a 10 kg child should
get the same absolute dose as a 100 kg adult.
> Can I broaden the discussion and ask whether people feel the adoption of
> body surface area dosing in oncology (or other disciplines) is appropriate,
> or should we strive to change the "dogma" and only correct for body surface
> area when it has been clearly shown to correlate with clearance.
I suggest you read something of the allometric literature (for a start
see the refs in the paper I cited earlier in this thread). The surface
area hypothesis of allometry is now widely discredited in favour of the
wt^3/4 model. I would support using wt^3/4 as a size scaling model until
it is shown to actually make things worse in some way. In general it is
absurd to imagine that clearance does not vary with size so I think one
should put this in your dose prediction model as a very strongly science
based 'assumption'. When large enough studies are done with wide enough
ranges of sizes it may then be possible to validate this assumption. I
think it is foolish to discard this good bit of science on the basis of
small studies with inadequate size ranges that cannot detect what we
know to be true i.e. clearance varies with size.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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