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Does anyone have had a PK model to describe time-dependent PK behavior?
AUC increased with time for day 1 to day 14 by 3 fold
It is know from in vitro assay that CYP450 is inhibited with time.
Amy (Xiaoping) Zhang, PhD.
PDMP, Clinical Pharmacology
340 Kingsland Street
Nutley, NJ 07110, USA
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Amy,
For reversible inhibition "one-way" effects are comparatively easy
to model if you know the baseline PK of the victim and the PK and
inhibitory potency (Ki) of the perpetrator you can predict the
effect upon clearance at any point. For two-way inhibition life
is a little more difficult.
For mechanism-based inhibition you'll need to characterise the kinetics
in vitro (K-big-I and k-inact) and then apply them with knowledge of
the turnover of the target enzyme. There's a nice paper by Bradley
Mayhew, David Jones and Stephen Hall (Drug Metab. Dispos. 28,
1031-1037 [2000]) that describes this. There's also a chapter in
"Drug-Drug Interactions" (Drugs and the Pharmaceutical Sciences:
Volume 116 [2002], edited by David Rodrigues) by Drs. Jones and Hall
that expands on the topic.
I hope that this helps.
All the very best,
Bernard
Bernard Murray, Ph.D.
Senior Research Investigator
Drug Metabolism, PCS, PPD, GPRD, Abbott Laboratories, Chicago, USA
Bernard.Murray.-a-.abbott.com
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Hi Amy,
I apologize if I sound simplistic but wouldn't you expect to see an
increase in AUC on day 14 compared to day 1? In other words, could it
simply be due to accumulation of the compound after repeated dosing?
Could you provide some more information on the dosing frequency and PK
properties of your compound?
If the inhibition is a fact, I would recommend a recent paper in Br J
Clin Pharm (Gordi et al.; 2005 Feb;59(2):189-98), where induction of
enzymes was modeled. I believe the same basic model can be used to
describe the inhibition upon minor modifications.
Toufigh Gordi
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Dear Amy,
The following code for Berkeley Madonna does what you describe,
increasing AUC from day 1 to day 14 more than a linear model would
accumulate. Through an indirect response mechanism It invokes a
feedback from the drug concentration to inhibit the formation of some
biosystem entity, upon which clearance is dependent. There is a
separate time constant for the biosystem turnover which will control
the rate at which the CL changes, and of course recovers afterwards.
If you are thinking of mechanism based inactivation of a CYP, then the
system turnover should be that of the cytochrome P450(s) responsible
for CL (or any transporter or other elimination mechanism for that
matter).
You should be able to paste this code directly into Berkeley Madonna
and see the result after running it. Then try overlaying concentration
profiles with kSYS=0.1 versus 0.0. Berkeley Madonna can be used in demo
mode free of charge (you cannot save results though).
Best regards, Phil.
METHOD STIFF
STARTTIME = 0
STOPTIME = 360
;
DT = 0.001
;Integration time step (Euler, RK2, and RK4 methods only)
TOLERANCE = 1e-3
;Relative accuracy for Auto and Stiff integration methods
DTMIN = 1e-3
;Minimum DT (Auto and Stiff methods only)
DTMAX = 0.1
;Maximum DT (Auto and Stiff methods only)
DTOUT = 0
;Output time interval (0 = store every step)
Dose= 1
;Can also set different doses for the different vectors if needed
StartT=24
;Start time (does not have to be zero; useful when doing PKPD)
Tau=24
;dosing interval
CLI = 0.2
;Typical CL Initially at t=0
CL = CLI*SYS
;CL at any point in time depends on level of something in SYStem
V = 7
;Typical V
ka = 0.5
;Typical ka
kSYS = 0.1
;time constant for biosystem turnover (set to 0.0 to have no turnover)
IC50 = 0.2
;degree of effect of drug on biosystem production rate
;Pulse dosing to (pseudo) steady-state
INPUT = PULSE(Dose,StartT,Tau)
;pulse dosing into whichever DE contains the INPUT statement
d/dt(A) = INPUT -ka*A
;A is absorption site
INIT(A) = 0
d/dt(D) = ka*A -D*CL/V
;D is drug (central) site
INIT(D) = 0
d/dt(SYS) = kSYS*(1-CD/(IC50+CD)) -kSYS*SYS
;SYS is some (relative) biosystem property,
INIT(SYS) = 1
;the production of which is affected by drug
;Calculate output Concentration Drug
CD = D/V
[Conversion to plain text may have caused some code changes - db]
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