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Dear all
in a bioequivalence study with a +/- 15% range of ideal body weight
(calculated using the Lorentz's formula) as inclusion criterium, the
Clinical Investigator accepted a volunteer with a + 18% body weight,
justifying his decision with the fact that the slightly higher body weight
was due to an increased muscle mass (this volunteer practices sports) and
not with an increased adipose mass, therefore not influencing the
pharmacokinetic behaviour of the drug (an antibiotic). Can anybody tell me
if this decision is correct and if there are any reference covering this
aspect?
By the way this volunteer showed lower plasma levels but comparable with
those of another subject with all the inclusion criteria satisfied (usual
critera of bioequivalence studies).
THank you for your help
Mauro Bertolino
LCG-RBM Italy
mauber.-at-.to.flashnet.it
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I think you are creating a problem for yourself by worrying over this. The
issue of being 18%
instead of 15% of IBW is probably comparable to worrying about whether to
report an AUC as 99.9 or
99.99.
Note that body structure itself (fat, muscle , etc) is not expected to
influence clearance of
bioavailability so if this subject had a somewhat lower AUC it would
reflect a higher clearance/lower
bioavailablity which would not be directly correlated with differences in
body composition. Body
composition may influence the apparent volume of distribution (perhaps
reflected in Cmax in your
study). There is no rule which would predict precisely which tissues may be
involved in determining
the apparent volume of distribution. Digoxin has a large volume which may
be attributed to binding to
skeletal muscle (at least in part) but otherwise I am not aware of any drug
whose Vd is specifically
detemined by muscle mass. It is frequently speculated that fat soluble
drugs will have larger volumes
in obese people and this is quite reasonable. Hard evidence is harder to
come by.
--
Nick Holford, Center for Drug Development Science
Georgetown University, 3900 Reservoir Rd NW, DC 20007-2197
email:n.holford.at.auckland.ac.nz tel:(202)687-1618 fax:687-0193
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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My understanding is that the basic reasoning behind the +/- 15%
acceptance range is to indicate health. Insurance companies seem to have
used similar criteria for life insurances. If your subject is practising
sports, and if everything else indicates that he in not unhealthy, there
should be no reason for not accepting him as a subject in a
bioequivalence study. The only problem you might have is to justify your
decision to the more bureaucratically inclined people that seem to be
infiltrating companies and regulatory bodies alike.
Olof Borga
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I ran into an instance where muscle weight actually played a role in
dopamine re-uptake metabolisms. Unfortunately, the correlations still
remain unexplained so I can't help you out further than to let you know
that you may have to take muscle weight into account.
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Hello all,
I don't know the necessity of all this argument about IBW.
Coz as far as i know in bioeq. studies they perform tests in a cross over
design. So, any probable faults about a person is corrected in this sort
of study.Please do notify me if I'm wrong.
Ahmad M.
Postgrad. Student
ahmadmir.aaa.nrcgeb.ac.ir
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Body mass is not an issue in bioequivalence study due to the cross-over
nature of study design. However, it could matter if the bioequivalence
study is a parallel study (sometimes preferable as recently discussed).
Thus, if you have a larger subject, he (most likely) would drive the mean
of AUC and Cmax for both the test and reference. Thus, the mean ratio
would be unchanged; of course that's if the kinetic of the drug was
influenced by body weight. If so, one way to control this factor would be
to normalize your parameters (or dose) per body weight if see if that
changes the results. I bet it doesn't matter.
Eric Masson, Pharm.D.
Directeur Scientifique
Anapharm Inc.
2050, boul. Ren=E9-L=E9vesque Ouest,
5e =E9tage,
Sainte-Foy, QC,
G1V-2K8
Tel: (418) 527-4000
FAX: (418) 527-3456
Email: emasson.-at-.anapharm.com
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Dear Ahmad:
The problem with so many ideal body weight formulas is that while they
make common sense and appear logical, most have not been verified, and many
are actually unverifiable. Body mass index is at least based on physiology,
and has correlated well with body density and with antipyrine space.
Because of this, it seems the best to me, and might well be used to compute
a fat-free body weight for use in cases where the drug either does, or
definitely does not, prefer to distribute itself in fat.
Sincerely,
Roger Jelliffe
************************************************
Roger W. Jelliffe, M.D.
USC Lab of Applied Pharmacokinetics
CSC 134-B, 2250 Alcazar St, Los Angeles CA 90033
Phone (213)342-1300, Fax (213)342-1302
email=jelliffe.at.hsc.usc.edu
************************************************
Take a look at our Web page for announcements of
new software and upcoming workshops and events!!
It is http://www.usc.edu/hsc/lab_apk/
************************************************
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[Three replies - db]
From: "David Nix"
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
Date: Fri, 15 May 1998 16:04:04 MST7
Subject: Re: PharmPK Re: Body mass problem in bioequivalence study
Priority: normal
I could not agree more with your comment about ideal body weight
formulas. Although these formulas are commonly used for drug dosing,
most studies do not evaluate whether they predict volume or clearance
better than actual body weight. The use of ideal body weight is
typically an add on to dosing guidelines although the mean PK
parameters were developed using actual body weight.
I am curious how you propose to use BMI as a measure of fat-free body
weight. BMI = weight (kg) / Height (m) ^2. A normal individual
would be considered to have a BMI of ~19 to 25 since individuals
with BMI below or above this range exhibit greater age
adjusted mortality. It is possible for a very muscular individual to
have a BMI of >25 with a very low percent body fat - this individual
would be misclassified as obese using BMI alone. Moreover, the
"normal" BMI may be higher in elderly patients. Of course the same
problems are evident with using only height to define LBW.
We could assume that a normal BMI is ~24 and this would be associated
with about 20% body fat (17% in males and 22% in females). Then a 68
in (1.73 m) tall male would be expected to weigh 72 kg with a lean
mass of about (72 X 0.83) 60 kg. However this reasoning again
reverts to using only height as a predictor of lean body mass.
I realize that the initial question pertained to use of strict weight
limits for entry into a bioequivalence study. I have performed many
Phase I studies over the years and someone always adds a weight limit
of +/- 10-20%. Particularily if 10% is chosen, the eligible
population becomes quite restricted. Lets face it, American's are
fat! When you add statements such as "all laboratory measurements
must be within the normal range", there can be much difficulty in
finding good subject. I often found myself excluding subjects that I
knew would be reliable and more cooperative with the study, simply
because they were 12% above the normal range. The FDA can site an
investigator if they enter patients outside of the specified
criteria of the protocol and they have been known to do so. I have
also entered subjects whom I did not feel would be a good
subject, because they did meet written criteria and there was
considerable pressure to get the study started quickly.
Usually the weight limit is defended by the "need" to have a
homogeneous population. However, I think that a representative
population is more important. The subjects should not be severely
underweight or obese, and they should be in good overall health.
However, it is important not to write protocols too restrictive for
the sole reason of being restrictive. In some texts, a BMI of >25 is
considered obese. I am 64 in tall and weigh 70 kg - BMI=26.3.
However, I am within 4% of the metropolitan life insurance tables.
To my knowledge, advantages of these very restrictive criteria have
not been established.
David Nix
---
From: Nick Holford
Sender: nhol004.at.auckland.ac.nz
Reply-To: n.holford.-a-.auckland.ac.nz
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Subject: PharmPK Re: Body mass problem in bioequivalence study
Date: Fri, 15 May 1998 20:28:11 -0400 (Eastern Daylight Time)
Priority: NORMAL
X-Authentication: none
MIME-Version: 1.0
Roger,
On Fri, 15 May 1998 13:26:19 -0500 Roger Jelliffewrote:
> The problem with so many ideal body weight formulas is that while they
> make common sense and appear logical, most have not been verified, and many
> are actually unverifiable.
Agreed.
> Body mass index is at least based on physiology,
Would you like to explain the physiological basis for body mass index? I
had always thought of it is
as an empirical covariate.
> Because of this, it seems the best to me, and might well be used to compute
> a fat-free body weight for use in cases where the drug either does, or
> definitely does not, prefer to distribute itself in fat.
I am not sure why you seem to recommend it as a predictor of fat-free body
weight. Isnt it supposed to be a
quantitative expression of obesity? How do you suggest it be used to
predict fat-free body weight?
> and has correlated well with body density and with antipyrine space.
Correlation is the weakest form of modelling. Is there any stronger reason
to use BMI?
Can you explain what is the pharmacokinetic relevance of "body density"?
I presume you mean antipyrine Vss when you refer to "antiypyrine space".
Would you please clarify what you mean and
also explain why a correlation of BMI with antipyrine Vss has any general
relevance to pharmacokinetic prediction? For
instance I would not expect antipyrine Vss to be a useful predictor of
digoxin Vss and as you know digoxin Vss is one
of the few instances where it has been shown that body fat does not
influence it to any clinically relevant degree.
Nick Holford, Center for Drug Development Science
Georgetown University, 3900 Reservoir Rd NW, DC 20007-2197
email:n.holford.at.auckland.ac.nz tel:(202)687-1618 fax:687-0193
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
---
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Mime-Version: 1.0
Date: Fri, 15 May 1998 23:13:38 -0400
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
From: Daro Gross
Subject: Re: PharmPK Re: Body mass problem in bioequivalence study
Roger,
Attempting to simplify the PK dynamics of a drug with respect to speed of
dissolution in fat can lead to a gross simplification of the PD of a drug.
Body weight is useful in measuring metabolisms that can be expected to come
into play when a drug is administered. Body weight cannot be linearly
related to the PK of a treatment protocol. This description does not
contradict your observations, but simpifies them to seek avenues for
exploring more direct relationships between physiology and a drug PK.
DG
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If a drug does not distribute into fat, then it may be limited to TOTAL
BODY WATER (TBW).
A nomogram for estimating TBW was published by Watson et al., Amer. J Clin
Nutr 33:27-39 (1980)
This was created using a Caucasian population.
This nomogram was successfully used by Thomasson et al to estimate doses of
ethanol (g/liter TBW) for an African-American college age population.
For men:
TBW (L)= 2.447- 0.09516 * age (yr) + 0.1074 * height (cm) + 0.3362 * weight
(kg)
For women:
TBW(L)= -2.097 + 0.1069 * height (cm) + 0.2466 * weight (kg)
Susan Shoaf
shoaf.aaa.clinpharm.niaaa.nih.gov|Nat'l Institute on Alcohol Abuse and Alcoholism
I don't speak for NIAAA, |Unit of Pharmacokinetic Studies
That's for the PR office |
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