Back to the Top
What's the latest on estimating the adjusted levels of phenytoin for someone
with low albumin AND renal failure? I have a patient who has both renal
failure (estimated creatinine clearance 12 ml/min per Cockroft-Gault) and an
albumin of 2.1. Her last total phenytoin level was around 18 and the
adjustment I come up with is rather high. The physician (neurologist) doesn't
seem too concerned about it. What exactly constitutes "uremia" which is
supposed to alter protein binding of phenytoin? Is it asssociated with going
below some specific creatinine clearance point?
The Winter-Tozer equation is for low albumin to make adjustments for what the
free level would be associated with if there was normal albumin. Is there
some estimation which accounts for both RF and low albumin? Does anyone just
bag this and get free phenytoin levels instead? At my hospital from what the
lab told me free levels aren't that much more expensive than total levels.
Why not just get free levels and forget about all this estimation stuff?
Do you all find most physicians unaware of these considerations ?
Randy
Back to the Top
I should advice to measure just free levels.
D.J. Touw, PhD
dj.touw.-a-.azvu.nl
Back to the Top
[db - two replies]
Date: Tue, 27 Jan 1998 13:43:30 -0500 (EST)
From: VINCENT EARL PEARSON
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
cc: Multiple recipients of PharmPK - Sent by
Subject: Re: PharmPK Phenytoin-Winter/Tozer Adjustments
MIME-Version: 1.0
Greetings!
According to the Clinical Pharmacokinetics Pocket Reference by John E.
Murphy, the following equation can be used for this situation:
Cp-normal = Cp-reported/[(0.483)*(serum albumin/4.4)+0.1]
The book, unfortunately, does not cite a reference specific to this
equation. "Uremia" refers to a buildup of blood urea nitrogen. I had
thought that uremia causes changes protein binding profiles, but I forget
the exact mechanism. However, this and similar equations tend to over and
underpredict concentrations (DICP 1989;23:64-8).
I hope this information proves useful.
With best regards,
Vince Pearson, Pharm.D., BCPS
Clinical Coordinator, Drug Information
The Johns Hopkins Hospital
Baltimore, Maryland USA
---
X-Sender: rjmeyer.aaa.globaldialog.com
Date: Tue, 27 Jan 1998 22:54:09 -0600
To: PharmPK.at.pharm.cpb.uokhsc.edu
From: Bob Meyer
Subject: Re: PharmPK Re: Phenytoin-Winter/Tozer Adjustments
Mime-Version: 1.0
Hi. I have a couple questions here. My first is that when you talk about
treating the patient and not the numbers, how do define a desired clinical
response? It's easy to tell when you're stopping the seizure activity, but
what about when you're trying to prevent it? One of our neurosurgeons
takes that line of reasoning to the extreme in interpreting a "therapeutic"
phenytoin level as whatever level is "preventing" seizures: if a person has
a less-than-detectable phenytoin level and is presently not seizing, he
feels that the patient has a "therapeutic" level. I've seen a number of
articles that address going well into the 20's or 30's with levels, and it
certainly seems justified (depending, of course, at what point the adverse
effects appear), but what do you think is appropriate at the low end for
prophylaxis? What exactly is the basis for the value of "10" to be used as
the low end of the range, and is it valid as such?
My other question concerns the correction from measured phenytoin for
albumin. As I'm sure you know, the equation that Parke-Davis provides
(measured/(alb x 0.2)+0.1) differs from what you present, is their's an
outdated version? It seems that yours takes a couple more variables into
consideration, does it seem to give a more accurate representation of
what's there?
Also, I appreciate the opportunity to peruse your web page on kinetics. It
seems interesting and I'm looking forward to spending some time with it.
Thanks,
Bob Meyer, RPh
Back to the Top
In regards to a recent question on phenytoin adjustments for uremic
patients, I had left a response regarding a assay error but not included
the references.
In 1995 we published a paper in The Annals of Pharmacotherapy
(July/August, Vol 29 pp 667) on predictability of the Winter-Tozer
Equation in patients with low albumins. We measured free levels seperated
at 37 degrees C via HPLC. During this time, we were also changing our
assay from HPLC to the Abbott TDx assay for phenytoin. We ran 15 total
phenytoin samples by HPLC and TDx in uremic patients and found that the
TDx results were about 60% higher then the HPLC determined serum
concentrations. Bias:4.28 Precision 22.16. All the patients had normal
Bilirubin levels (this can also impact your results).
We then checked the literature, and found a paper by Roberts and Rainey
(Clinical Chemistry 1993;39(9):1872) titled "Interference in Immunoassay
Measurements of Total and Free Phenytoin in Uremic Patients: A
Reapprasial".They looked at both the TDx aca, EMIT, and HPLC assays,
finding a positive bias in the TDx for both the free and total phenytoin
levels due to cross reactivity from a possible minor metabolite. Total:
TDx = 1.24 X HPLC + 1.9 mg/l) Free: TDx = 1.52 X HPLC + 0.24 mg/l). Thus,
the free level via TDx is also in error, and results should be used with
caution in Uremic patients.
I agree with the approach of treating the patient, not the level, but if
you use the equation to normalize phenytoin in uremia of
PHT Corrected = PHT Measured/0.1(Albumin) + 0.1) (TDx Assay)
you will overpredict the corrected level considerably. It's actually
clinically close enough to just use the nonuremic correcting equation
(PHT Corrected = PHT Measured/0.2(Albumin) + 0.1) when using results from
the TDx assay. Free levels are expensive, and hard to trust in uremia.
Just another example of how things change in medicine just when we thought
we had it all worked out. Wait until some one asks about Vancomycin in
Uremia (another significant assay error, but that's a different debate).
William Dager, Pharm.D., FCSHP
Coordinator, Pharmacokinetics Consult Service
U C Davis Medical Center
Back to the Top
Dear Randy
Most physicians are either unaware or unconcerned because what they
don't know won't hurt them. Get the free levels! It is about the only
way you can prove to a physician that the patient is pharmacologically
toxic despite lack of clinical toxicity. Free phenytoin levels greater
than 2.5 to 3.0 mcg/ml are probably going to cause damage to the
cerebellum. If this is continued for a long time (how long? months to
years) the damage is irreversible. Good luck!
Ron Floyd, PharmD--radfloyd.-at-.pacbell.net
Back to the Top
On Tue, 15 Sep 1998 10:02:43 -0500 by way of David_Bournewrote:
>
> Most physicians are either unaware or unconcerned because
> what they don't know won't hurt them. Get the free levels!
> It is about the only way you can prove to a physician
that > the patient is pharmacologically toxic despite lack
of > clinical toxicity.
Huh? What kind of BS is this pharmacologically toxic vs
clinical toxicity? Is this toxicokinetics in action? :-)
> Free phenytoin levels greater than 2.5
> to 3.0 mcg/ml are probably going to cause damage to
> the cerebellum.
Can you provide details of the evidence to support this
statement that would be very important if it was true?
If this is continued for a long time (how
> long? months to years) the damage is irreversible.
Only speculation..
--
Nick Holford, L226,Dept of Neurology,OHSU
3181 SW Sam Jackson Park Road,Portland,OR 97201-3098
n.holford.-a-.auckland.ac.nz,(503)494-4778,fax 494-7242
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)