Good morning I have written a software program for a handheld computerBack to the Top
to reflect the new renal dosage guidelines for Lovenox. As I review
obesity and Cr Cl with the Cockcroft-Gault equation I would appreciate
some guidance about what is obesity for various medications not just
Lovenox.
My current view is that excessive adipose tissue can alter the
pharmacokinetics of drugs by changing the volume of distribution. Meds
that have high lipid solubility have larger Vd\0xEDs in obese patients and
the Vd\0xEDs with water soluble meds is not significantly different in
obese and normal weight patients. I would like to set different obesity
factors for various medications.
This CrCl calculator will not be used for peds or patients that have
unstable CrCl ( Jelliffe ) or for
Gent or Vanco dosing. The only meds planned at present are Integrilin,
Refludan, Tikosyn and Lovenox.
From the Lovenox package insert:
Weight: After repeated subcutaneous 1.5 mg/kg once daily dosing, mean
AUC of anti-Factor Xa activity is marginally higher at steady-state in
obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese
control subjects, while Amax is not increased.
When non-weight adjusted dosing was administered, it was found after a
single-subcutaneous 40-mg dose, that anti-Factor Xa exposure is 52%
higher in low-weight women (<45 kg) and 27% higher in low-weight men
(<57 kg) when compared to normal weight control subjects.
My primary question is what criteria should I use for a medication to
set the factor for comparing
gvLWtKg to gvLLBW ?
The second question is the same for calculating gvLAdjBW add 20% or 40%
based on what criteria?
Or would I best serve my end user by just setting the factor to 1.3 and
0.3 and not worry about this issue?
I have also limited the end user from entering a Sr Cr for a female of
less than 0.6 mg/dL
and less than 0.8 mg/dL for a male.
Is this appropriate or would 0.9 mg/dL male or female be more realistic?
Below are the calculations for Cr Cl Lovenox at present.
gvLWtKg is the patient\0xEDs real weight in Kg
gvLAge must be > 18 years
For Male Pt gvLSex = 1
gvLYF = 1
For Female Pt gvLSex = 0
gvLYF = 0.85
gvLLBW = Round(45.5 + ( gvLSex * 4.5) + (2.3 * (gvLPtInches-60)),1)
If gvLWtKg > (gvLLBW * 1.2) Then
'+20% Correct for obesity
gvLAdjBW = Round(gvLLBW + (0.2 *(gvLWtKg-gvLLBW)),1)
Else
'LBW used to calculate CrCl
gvLAdjBW = gvLLBW
End
'gvLCrCl = Round((140- gvLAge) * gvLAdjBW/(72*gvLSrCr) * gvLYF,1)
thank you in advance for all replies
please understand I will not quote anyone in my software
in case Adventis research folks are reading
direct replies are fine with me if this is too far off topic
if you would like to beta test for free I would be happy to
send anyone a copy of the program
dwight norris r.ph.
dnorris.aaa.fireserve.net
Back to the Top
My apologies I have omitted a line or two of code from my original post
please see below this is the code that was omitted
'Decrease LBW if LBW > Actual weight
If gvLLBW > gvLWtKg Then
gvLLBW = gvLWtKg
End If
dwight norris r.ph.
Back to the Top
Dear Dwight,
You raise this question at a timely moment, as I have some experience
of dosing Lovenox in the obese, and have a review seeking to answer
some of your general questions that is in press.
Whilst conducting research in the obese, our group has questioned which
of the various size descriptors presented in the literature best
explains between subject variability in V and CL. we have found that V
is best described by total body weight, and CL by some other descriptor
that excludes excess fat i.e. lean body weight or fat free mass.
Loading doses may need to be increased in the obese if the drug is
lipophilic, although maintenance doses need not be adjusted, unless the
drug has some unusual characteristic where it is metabolized in the
fat. For drugs that are hydrophilic such as enoxaparin (Lovenox), no
change in dose strategy between the obese and normal weight patients
seems warranted if you consider dosing on some estimate of lean mass.
If you are dosing on total body weight then of course you need to
change the dose at some cut off point where the ratio of fat to lean
mass results in excess concentrations. This is particularly important
for Lovenox, as higher concentrations can cause severe bleeding. You
might want to look at the following for further information;
Green B, Duffull S. Development of a dosing strategy of enoxaparin for
obese patients. British Journal of Clinical Pharmacology 2003; 56:
96-103
Regards
Bruce
Bruce Green
Research Fellow
Center for Drug Development Science
Georgetown University Medical School
3900 Reservoir Rd. NW Med-Dent NE412
Washington, DC 20057
phone: +1 202-687-0310
fax:+1 202-687-0193
Back to the Top
Dwight,
What I have always done, what I teach my students and what I
incorporated
into my program is the following:
When using the Cockcroft & Gault equation, there original work was done
using actual body weight. However, when you look at their individual
patients, you will notice that are all within 10% of lean body weight,
so if
they had regressed with lean body weight, they would have come up with
almost the same regression relationship. The production of creatinine
is
in the muscles and it is produced at a fairly constant rate. With the
exception of body builders, usually muscle mass is not increased as
weight
goes up in obese individuals. Based on that, it would make sense that
CrCl
estimates using the Cockcroft and Gault relationship should use lean
body
weight, not actual weight (unless actual weight is less than lean body
weight) and not an adjusted weight.
The weight adjustment I use when determining population estimates of
volume
of distribution. When the population estimate of Vss is L/Kg, then I
use a
corrected body weight for obesity (greater than 30% over lean body
mass) if
the drug lipophobic - hence will not penetrate into the body fat. In
addition to the fat cells associated with obesity, there is interstitial
fluid. That interstitial fluid is estimated to be about 40% of that
excess
body weight. Therefore, the corrected body weight that I use for
volume of
distribution is lean body weight plus 40% of the excess weight) BWcor
= LBW
+ 0.4(ABW-LBW).
So, lookng at your equations below, the threshold I use for obestity is
30%
greater than lean body mass, and the correction is 40% of the excess
weight
and that corresponds close to the amount of interstitial fluid in that
excess weight. The other point that I would differ with you is on the
use
of the adjusted weight in the CrCl estimate. It does not make sense to
me
because usually muscle mass does not change with an increase in weight
and
it is not distributed into adipose tissue. It seems to me that you
need to
use either ABW, which is what Cockcroft & Gault technically did or you
use
LBW which is what that apparently did by including only patients within
10%
of their lean body mass.
Hope this helps,
Ron Herman
Back to the Top
For CrCl in obese individuals, it is best to use a method _derived_ in
obese individuals: Salazar-Corcoran. Adjusted body weight (40% of
excess
weight, blah, blah, blah) was derived _specifically_for_aminoglycosides_
when computing an initial volume of distribution estimate, and shouldn't
be assumed to be a universal solution for obesity. For instance, the
correction factor for phenytoin >1, presumably because the drug is lipid
soluble. --Larry
Back to the Top
Ron thanks this ties all the parts of the puzzle together
and gives me an idea of how Vd, obesity and the CG equation relate to
the
issue at hand
so I will try some numbers with your recommendation and change the
equation
as well
thanks for your time
dwight
Dear Larry and all, about CCr in obese people:Back to the Top
I have thought that lean body weight would be useful in this,
but I have been wrong more often than right, anecdotally, at least, and
so I have simply continued to use raw body weight.
That is one thing. Another is to estimate CCr when serum
creatinine is changing, not stable. This occurs often in acutely ill
and unstable patients. You might look at
Jelliffe R: Estimation of Creatinine Clearance in Patients
with Unstable Renal Function, without a Urine Specimen. Am. J.
Nephrology, 22: 3200-324, 2002.
Very best regards,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine,
Division of Geriatric Medicine,
Laboratory of Applied Pharmacokinetics,
USC Keck School of Medicine
2250 Alcazar St, Los Angeles CA 90033, USA
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.at.usc.edu
Our web site= http://www.lapk.org
Back to the Top
Thanks Larry and Roger
I am always impressed and in awe when I have answers from folks that I
own
book by
Applied Clinical Pharmacokinetics and authors of CrCl equations.
My real dilemma here is not using the wrong calculation and getting to a
CrCl < 30 mL/min
slower or faster than I should hence my software becomes misleading
I think I might like to drop Aventis a line and pray a lot they tell me
how
they calculated
this in the re-study of Lovenox
While this will only apply to a small percentage of patients I would
still
like to be as exact as possible.Some how this is what we get paid for,
being
exact.
Thank You all for letting a novice join in now and then
dwight norris r.ph.
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)