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Dear All,
What are important pharmacokinetic parameters one
should consider when selecting a lead during the early
phase discovery?
All suggestions are welcome.
Reagards,
JIM
Jim,Back to the Top
We posed the same question when we needed to define what parameters PK
Solutions should produce to be thorough. Our approach was to undertake
a survey of which parameters were most commonly reported in the general
literature on descriptive pharmacokinetics. To do this, we tabulated
all the PK parameters used in all the pharmacokinetics-related papers
published over a five-year period in both the Journal of Pharmacy &
Pharmaceutical Sciences and Drug Metabolism and Disposition. We then
included every parameter that occurred in >2% of all the publications
in our software, and then some.
You can read and download a free list of these parameters and
equations from our web site at:
www.SummitPK.com
Follow the link to "PK Equations".
Regards,
David
/\ /\
SummitPK.com /\ / \ /\ / \
/ / / /\ / \
David S. Farrier, Ph.D.Phone:970-249-1389
Summit Research ServicesFax:: 970-249-1360
68911 Open Field Dr.Email:DFarrier.-at-.SummitPK.com
Montrose, CO 81401Web: http://www.SummitPK.com
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Jim,
I have received a lot of criticism for what I about to advise, since it
is viewed as being too simplistic. If you are referring to a
conventional drug, select the one with the greatest degree of protein
binding (all other relevant information being equivalent). This will
most likely provide a compound with low clearance, which usually
translates into once daily, once weekly, etc. dosing. Also, when low
clearance compounds have their metabolism inhibited, the increase in
plasma concentrations is less than with higher clearance compounds.
For example, when mibefradil was on the market (a potent 3A4
inhibitor), it caused deaths only with high clearance 3A4 metabolized
statins, not the moderate clearance 3A4 metabolized statins. See this
article for a discussion:
http://www.ualberta.ca/~csps/JPPS2(2)/H.Boxenbaum3/Cytochrome-
Boxenbaum.pdf
Jim:Back to the Top
This is a very practical and tricky question. In general, Clearance and
Half life are two important parameters. CL determines the dose level,
whereas the half life determines the dosing frequency. The tricky part
is that many good leads are lipophilic compounds, which sticks to
tissue compartment, resulting in extremely long apparent terminal t1/2.
You may want to also look at MRT to help ranking compounds.Also, CL
needs adjusted for effective concentration for relative comparison.
www.pkpdonline.com
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Dear Clerk,
IMHO, your view is indeed too simplistic.
1) High protein binding is not necessarily associated with low
clearance. Of
course, an increase of protein binding results in a decrease of
clearance,
but this is not equivalent to your statement.
2) Low clearance is not necessarily associated with a long half-life
(and
consequently, a long dosing interval). For low-extraction drugs
half-life is
hardly dependent on protein binding and for high-extraction drugs
half-life
decreases with increasing protein binding, because increased protein
binding
results in a decrease of the volume of distribution.
3) Your remark with respect to inhibition of metabolism does not seem
to be
correct. I have not read the paper by Boxenbaum in detail, but my
conclusion
is that the CYP3A4 inhibitor reduced the intrinsic clearance by a
factor of
37 (this is indeed a dramatic decrease!). However, if the drug would
have
been a low extraction drug due to a lower protein binding, the decrease
of
intrinsic clearance would have been also by a factor of 37 (assuming
everything else the same), systemic clearance would be decreased by a
factor
of 37, and thus the average plasma concentration would also be 37 times
higher. This has little or nothing to do with the extraction ratio.
Perhaps Harold Boxenbaum can comment upon this?
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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Dear Hans:
You stated that "ecause increased protein binding results in a
decrease of the volume of distribution". Could you let me know if this
is
an observed fact or a hypothesis derived from theory? Could you let me
know
the reference discussing the relationships between protein binding and
volume of distribution? Thank you very much.
Ta Kung Chen, Ph.D.
Associate Director, Pre-Clinical Development
Neurocrine Biosciences, Inc.
10555 Science Center Rd.
San Diego, CA 92130, USA
Phone: 858 658-7726
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Takung,
The simplest relationship is: Vd = V(B) + [ V(T) x (fb/ft) ], where Vd
= volume of distribution; V(B) = volume of blood; V(T) = volume of
other tissues; fb = unbound fraction in blood; and ft = weighted
unbound fraction is tissues. As plasma protein binding increases, fb
gets smaller, and Vd gets smaller. The reference is: Wilkinson GR,
Shand DG, A physiological approach to hepatic drug clearance, Clin
Pharmacol Ther 18:377-390, 1975. Happy PK parameter computing! Harold.
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Hi Hans,
"Clerk" and me (Harold Boxenbaum) are bioequivalent.
I was joking with my wife to name our daughter "Clerk" after the
famous physicist "Clerk Maxwell," but alas, she was adamant that we
settle for Shelby Ariella Boxenbaum. Hense the name of my consulting
firm is "Arishel," which is a consolidation of Shelby Ariella
backwards. Perhaps Maxwell's demon is getting the better of me!
Yes, I agree with you. Its just that drugs with binding > 99
%empically seem to have low clearance, and long terminal exponential
half-lives. You can see this by scanning the index to Goodman and
Gilman, where the Univ of CA review PK parameters. The plasma protein
binding hybridization of CL and Vd just seem to provide a mix that
leads to drugs with low CL and long T-1/2values (empically, but no
doubt due to theoretical underpinnings). On the other hand, the long
T-1/2 of azithromycin in humans is primary due to a very large Vd,
since clearance is about 10 mL/min/kg (or somewherein that vicinity --
in other words, the Vd is more important in producing thelong T-1/2
than the CL).
With respect to high clearance drugs, I assume protein binding is
unchanged. Under this condition, what I said is correct. Check the
article and you will see this is true. The primary reason high CL
drugs have greater increases in AUC and Cav with metabolic inhibition,
is primary due to the change in first-pass hepatic extraction (ER,
assuming linear kinetics) -- see the article. Interestiing, Geoff
Tucker seems to have reached the same conclusion, as I have seen the
same shape plot in guidelines, which always seem to bear his name (and
maybe too in one of his articles). Of course, if I made an error in
the paper, please advise. However, be gentle, or I shall sick my
attack cat on you! She travels well in hyperspace ...
Think of you often with your wonderful method for switching between
linear and log trapezoidal rules (I think this was incorporated in
WinNonlin, or a method analogous to it). I wonder who the reviewer
providing the accolades of that manuscript was ...........
Hope life in the Netherlands is as wonderful as I remember my trip
toAmsterdam, about 15 or more years ago.
Best wishes. Harold.
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Hans et al,
Just as an aside, I recommend azithromycin beconsidered in clinical
studies where a "macrolide" or simimlar antimicrobial is indicated (so
patients can continue in the clinical study, and not be dropped
willy-nilly due to concomitant therapy - for example if a patient in a
long-term cholesterol lowering study develops an infection sentive to
azithromycin). This is because azithromycin does NOT inhibit CYP3A4,
in contradistinction to drugs such as erythromycin and clarithromycin.
Harold.
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May I ask if azithromycin would promote gastric motility like
erythromycin?.
If so it could affect tmax and Cmax.
Andrew Sutton
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My thought would be no. Azithro should not be stimulating the GI
receptors responsible for increased motility like erythro and
clarithro.
Greg
Greg Soon
Pharmacist-Critical Care
Peterborough Regional Health Centre
1 Hospital Drive
Peterborough, ON, Canada K9J 7C6
tel: 705-743-2121 x.3196
fax: 705-876-5072
page: 705-748-8592 (voice)
email: gsoon.at.sympatico.ca
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