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The following message was posted to: PharmPK
hi all
i am working on Pharmacokinetic and Pharmacodynamic interaction
studies of a contraceptive in rats when an antibiotic is
co-administered(both antibiotic and contraceptive are given
orally).
During the course of my study with antibiotic+Contraceptive i
observed that in 80% of my test animals, antibiotic is interacting
and resulting in contraceptive failure.(pharmacodynamic
interaction)
pharmacokinetically AUC is unchanged, there is increase in half
life by 6 h,but Vd/f and Cl/f are unchanged after antibiotic
co-administration..
is it unusual???? should there always be a PK interaction for a PD
interaction to occur?? if not can someone quote an example where
PD is altered though PK is more or less similar???
thanks in advance
vipul
Pharmacokinetics and Metabolism division
CDRI.Lucknow (India)
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At 06:29 AM 8/25/2003, Vipul Gupta wrote:
pharmacokinetically AUC is unchanged, there is increase in half
life by 6 h,but Vd/f and Cl/f are unchanged after antibiotic
co-administration..
If half-life is increased significantly but AUC is unchanged, then
average concentration must be down. Does the lower concentration fall
below the minimum effective concentration for the contraceptive?
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.at.simulations-plus.com
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The following message was posted to: PharmPK
Dear Vipul Gupta,
You wrote:
> pharmacokinetically AUC is unchanged, there is increase in half life
> by 6 h,but Vd/f and Cl/f are unchanged
This is rather curious. If Cl and Vd are unchanged, half-life should
also be unchanged. Probably you mean that Cl and Vd were not
significantly changed, but half-life was significantly changed. If so,
there must be some change in Cl and/or Vd.
> should there always be a PK interaction for a PD
> interaction to occur?
No. A purely pharmacodynamic interaction is characterized by an altered
effect and unchanged pharmacokinetics. I am not sure about real-life
examples, but any two drugs affecting the same 'drug effect' will show
a pharmacodynamic interaction, either additive, synergistic or
antagonistic. Your example is a special case, i.e. an (PD?) interaction
by a drug that does not give the same drug effect (I trust the
antibiotic drug is not contraceptive by itself; however, one never
knows if not tested!). If the interaction is not at the PK level, the
antibiotic may possibly affect the binding of your drug with its
receptor, the signal transduction, or whatever step eventuallt leading
to the effect (i.e. contraception).
In reply to your message Walt Woltosz wrote:
> If half-life is increased significantly but AUC is unchanged, then
> average concentration must be down.
I don't agree. If AUC is unchanged, the average concentration is
unchanged. And if the observed increase of half-life is a result of a
decreaed clearance, then the average concentration would be increased,
not decreased.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.aaa.farm.rug.nl
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At 11:54 PM 8/25/2003, you wrote:
"I don't agree. If AUC is unchanged, the average concentration is
unchanged. And if the observed increase of half-life is a result of a
decreaed clearance, then the average concentration would be increased,
not decreased."
My reasoning was that if half-life is longer, then the plasma
concentration-time curve must be lower to get the same AUC, which would
mean the average concentration is lower. How else could one have a
longer half-life and the same AUC????
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.aaa.simulations-plus.com
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The following message was posted to: PharmPK
Dear Walt,
You wrote in reply to my comment:
> My reasoning was that if half-life is longer, then the plasma
> concentration-time curve must be lower to get the same
> AUC, which would mean the average concentration is lower.
The average concentration is by definition AUC/tau where AUC is the area
under the curve during a single interval at steady state (and equals the
total AUC to infinity after a single dose, provided that clearance is
constant) and tau is the dosing interval.
> How else could one have a longer half-life and the same AUC????
If the volume of distribution is increased, half-life is longer and AUC
is
unchanged.
Please note that this refers to the data of a single subject. When
dealing
with mean values, the situation is more complex, since these simple
relationship do not hold exactly because of variability (using geometric
means is advantageous here, since the relationship t1/2 = ln(2) * V / CL
holds for geometric means, not for arithmetic means). In addition, the
meaning of 'increase', 'decrease' and 'equal' are used in a different
way,
i.e. in a statistical way. This was already mentioned in my previous
mail.
E.g., t1/2 may be significantly increased, but CL, V and AUC may be not
significantly different. This is not at all a strange situation, and is
not
in conflict to 'basic pharmacokinetics'.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.aaa.farm.rug.nl
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The following message was posted to: PharmPK
Dear Vipul,
"pharmacokinetically AUC is unchanged, there is increase in half
life by 6 h,but Vd/f and Cl/f are unchanged after antibiotic
co-administration.."
I have the same opinion of Walt Woltosz....and seeing that
Vd/CL = 1/Ke =[half-life]/[ln (2)]
overall elimination is unchanged if Clearance (CL) and volume of
distribution (Vd) are unchanged.
Probably you have an incorrect estimation of terminal half-life (i.e. a
compartmental analysis instead of non-compartmental analysis with a
flip-flop effect of ka vs. ke, etc.)
Regards
Stefano Porzio
Pharmacokinetic & Tox. Dept.
Inpharzam Ricerche SA
Zambon Group
Switzerland
stefano.porzio.-at-.zambongroup.com
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The following message was posted to: PharmPK
Dear Vipul Gupta,
I have seen response of many experts on this problem. With due respect
to their knowledge and expertise I would like to add here is the basic
mistake in conceptualization of the problem. The use of term
PHARMACODYNAMIC interaction is misleading here unless one specifies if
he or she has monitored the interaction at recptor level if we go by
definition of PHARMACODYNAMICS, its like considering APPLES as ORANGES
(Hope Prof Nick would pardon me for using this analogy). I am sure if
you have monitored the contraceptive failure as a marker of the
interaction then it is purely a PHARMACOLOGICAL interaction unless
otherwise specified. As far as the PK interaction is concerned you
should put some numbers and statistics for others to compare simply by
saying that half-life was 6h more will not help anybody guess about the
comparison. I dont know what program you are using to calculate the
half-life but you need to be careful in computing the half-life, if one
is not careful enough during data analysis it may lead to bias since you
say that Cl and Vd and AUC are not changed. I would say that in such a
case it is a better idea to stick to the Cl and Vd for comparison rather
than the half-life.
Hope this helps
Good Luck
Manoj Khurana
Manoj Khurana, Ph. D.
Post Doctoral Fellow
Pharmacokinetics Biopharmaceutics Laboratory,
University of Maryland Baltimore
Rm 503B, HSF-II Building
20 Penn Street, Baltimore, MD 21201
100 Penn Streeet Baltimore, MD-21201
Ph: 410-706-1133
Fax: 410-706-6580
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I think one way to explain this is to see if the t1/2 you are
considering is indeed the effective t1/2 rather than terminal t1/2. If
you have multiphasic elimination, often the contribution of terminal
t1/2 is very small to the total AUC. In that case, the terminal t1/2
can change, let us say from 100 hours to 300 hours, this can still
mean very little in terms of change in AUC.
Soraya Madani, PhD
Novartis Pharmaceutical Corp.
Early Clinical Development (Pharmacokinetics)
59 Rt 10
East Hanover, NJ 07936-1080
Tel 862-778-5059
Email: soraya.madani.aaa.pharma.novartis.com
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Dear Hans,
At 11:41 PM 8/26/2003, Hans Proost wrote:
"How else could one have a longer half-life and the same AUC????
If the volume of distribution is increased, half-life is longer and AUC
is
unchanged."
But if Vd is increased, then the average concentration will decrease,
all other parameters remaining the same.
You refer to AUC over a dosing interval, rather than (0-inf). It
appears that is where the confusion lies. I assumed the original
posting referred to AUC (0-inf).
With a longer half-life, AUC (0-inf) will be the result of a plasma
concentration-time curve that stays above "zero" for a longer time. To
maintain the same AUC, in order to offset the additional area under the
curve at the later times, the initial concentrations will have to be
lower - hence, average concentration should be lower. You can't have an
average concentration of 10 for 10 hours, and then an average
concentration of 10 for 20 hours, and get the same AUC.
But if you look only at the AUC for 10 hours, then clearly the same AUC
for 10 hours implies the same average concentration for 10 hours.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.aaa.simulations-plus.com
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The following message was posted to: PharmPK
Walt Woltosz wrote:
"But if Vd is increased, then the average concentration will decrease,
all other parameters remaining the same."
I disagree. The average steady state concentration is determined ONLY
by clearance (and F). It is not affected by volume of distribution.
Rate In = Rate Out = CL/F * Css
Css = Rate In * F/CL
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
Hello,
In mho, we should define the parameter of interest since it seems that
different parameters are referred to as "average concentrations". It
seems correct to assume that increasing volume (without any change in
CL) will result in lower concentrations, higher thalf and no change in
AUC. However, Css,average will not be affected since it is governed by
dose, bioavailability, CL, and dosing interval (and not volume of
distribution). I assume Walt refers to the "average concentrations" as
seen after a single dose in several subjects, whereas Hans talks about
the Css,average, which is the average steady state concentrations
reached in the same subjects upon repeated dosing. In the latter case,
when Vd increases, Css max and Css min decrease and increase,
respectively, although Css average stays the same.
Toufigh Gordi
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The following message was posted to: PharmPK
My intuition is that in cases of severe sepsis even if clearance (and
F)stayed constant there would be a change in actual volume that would
affect
concentration. [Of course, I doubt that clearance (and fudge factor F)
would
remain constant under such circumstances. This is a hypothetical to
make a
point regarding a variable that could be independent.]
Meyer
Meyer Katzper, Ph.D.
FDA/CDER/ODEV/DAAODP
katzper.-a-.cder.fda.gov
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The following message was posted to: PharmPK
Walt Woltosz wrote:
"But if Vd is increased, then the average concentration will decrease,
all other parameters remaining the same."
Nick Holford wrote:
"I disagree. The average steady state concentration is determined ONLY
by clearance (and F). It is not affected by volume of distribution.
Rate In = Rate Out = CL/F * Css
Css = Rate In * F/CL"
Why do you assume steady state?
For a single dose, there is generally no true steady state. If the
volume is doubled, but CL and F remain the same, then it seems the
concentration must go down - the same number of drug molecules occupies
a larger volume, and mass/volume = concentration.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.aaa.simulations-plus.com
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The following message was posted to: PharmPK
Dear Walt,
The notion of changing/not changing in Css or AUC is true even in the
case of a single dose. If Vss is changed, let's say doubled, but CL is
unchanged, what will happen will be the following:
AUC will remain unchanged since: AUC=Dose/CL (I am assuming iv dose,
but it should be the same for other routs of administration). If
neither Dose nor CL change, obviously AUC will not change.
C0, i.e. concentration at time zero will decrease since C0=Dose/Vd. So,
as you mention, the concentration will decrease. However, since the
elimination rate constant decreases with an increase in Vd (ke=CL/V),
and thereby thalf is increased (thalf=ln(2)/ke), what happens is that
as time passes, the concentrations will decrease slower compared to
when Vd is not changed. If one collects samples long enough, it is
obvious that as time passes the concentrations at situation 2
(increased Vd) will be higher that the original state(original Vd).
In summary, when an increase in Vd takes place, the initial
concentrations will be lower than those observed with the original Vd
but terminal concentrations will be higher than what would be with the
original Vd.
Toufigh Gordi
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The following message was posted to: PharmPK
>
> Walt Woltosz wrote:
>
> "But if Vd is increased, then the average concentration will decrease,
> all other parameters remaining the same."
>
> Nick Holford wrote:
>
> "I disagree. The average steady state concentration is determined ONLY
> by clearance (and F). It is not affected by volume of distribution.
>
> Rate In = Rate Out = CL/F * Css
>
> Css = Rate In * F/CL"
>
> Walt Woltosz wrote:
> Why do you assume steady state?
>
I chose steady state because I think the concept of an average steady
state concentration is well understood. In this case, your assertion
that volume affects average concentration is provably incorrect.
On the other hand what do you mean by average conc for non-steady
state? Please tell me how you plan to compute the average. One
possibility would be to compute if from AUC/t. The average would depend
on the AUC integration limits and the influence of V would vary with
time.
> Walt Woltosz wrote:
> For a single dose, there is generally no true steady state. If the
> volume is doubled, but CL and F remain the same, then it seems the
> concentration must go down - the same number of drug molecules occupies
> a larger volume, and mass/volume = concentration.
>
Your mass/volume calculation does not seem realistic to me. It seems to
imply that at some time after giving the dose the volume is somehow
instantaneously doubled. I would agree that if this happened then conc
would fall. But this is not a realistic pharmacokinetic situation.
For any practical meaning I think we need to consider the situation of
the time course of drug conc on two separate occasions with different
volumes on each occasion. In this case the conc at any given time can
be lower or higher when volume is doubled e.g. at time zero after a
bolus dose the conc will be halved but after 1.44 half-lives the conc
will be higher. At 1.44 half-lives the conc will be identical and
independent of volume.
IMHO there is no useful interpretation of an average concentration in
the non-steady state situation without explicitly defining the times
over which concentrations are to be averaged.
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
Dear Meyer Katzper and Walt Woltosz,
Meyer Katzper wrote:
> My intuition is that in cases of severe sepsis even if clearance (and
> F)stayed constant there would be a change in actual volume that would
> affect concentration.
As has been clarified by Toufigh Gordi and Nick Holford, a change in
volume
of distribution does not affect the average concentration at steady
state. I
fully agree with them.
I trust that you refer to the PEAK concentration. Indeed, peak and
trough
concentrations are affected by the volume of distribution. An increased
volume of distribution results in lower peaks and higher trough levels
if
the dose and dosing interval are unchanged. In cases where the AVERAGE
concentration is most relevant for the therapeutic effect, there is no
need
to change the dose or interval, and the lower peaks and higher trough
levels
may be advantageous with respect to get a more constant effect and
lower the
risk of side-effects.
On the contrary, if the peak concentration is relevant for the drug
effect,
e.g. for several antibiotics (as used in patients with sepsis), it may
be
necessary to increase the dose to compensate for the lower peak levels;
the
question whether or not the dosing interval should be increased is a
different topic. In this cases volume of distribution is indeed a
relevant
parameter for the optimal dosing schedule.
Perhaps this difference between average level and peak level is also the
basis of the discussion between Walt Woltosz and others (including me).
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-at-.farm.rug.nl
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