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Can someone explain me or quote a reference, for drugs like carbamezapine, where autoinduction takes place, how to consider this factor while developing a statistical model to simulate single dose PK data to steady state PK?
regds
shefali
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Shefali,
If you have both single dose and some repeat dose data in a range of doses, you can built a compartmental model for the drug and indirect response model for the metabolizing enzyme, where drug clearance depends on the amount of enzyme, production of which increases with drug concentrations. You do not need to measure enzyme concentrations to be able to estimate parameters of this system. If the repeat dose data you have is when induction has been already completed, you may need to fix the parameter responsible for onset time and only estimate EC50 of induction. If you only have single dose data, whether you'll be able to estimate parameters of induction depends on how fast the elimination of the drug is - whether time that drug is in the system in appreciable concentrations is enough to show apparent nonlinearity of elimination. If you can not estimate the parameters, you'll have to make assumptions based on what you know about the drug, enzyme, and similar compounds/enzyme systems, fix induction parameters t
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Hi Shefali
You may find the following paper useful:
Magnusson MO, Dahl ML, Cederberg J, Karlsson MO and Sandstrom R (2008) Pharmacodynamics of carbamazepine-mediated induction of CYP3A4, CYP1A2, and Pgp as assessed by probe substrates midazolam, caffeine, and digoxin. Clin Pharmacol Ther 84:52-62.
Regards
Masoud
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The following message was posted to: PharmPK
Hi Katya, your response was helpful as I am also working on an autoinduction model for an NCE.
Can you give me some advice on the model below, i have a 2 CPT PK model and an indirect response relationship witht the emperical enzyme compartment like you described. I have multiple dose data over 14 days and know that the compound is metabolized by CYP3A4 which should have a KOUT of 0.029hr-1. The problem is that I mostly end up with unreasonable estimates for KOUT EC50 EMAX and/or Volumes in different combinations.
Also what is Emax in my case? Is it the makimal increase in amount of enzyme (and therefore Clearence) eg if my enzyme increases from 1 unit to a maximum of 2.5 does that mean i have 2.5 fold effect or increase in Clearance?
I will greatly appreciate your comments and any examples you can share with me. I have not been able to get the complete picture from literature.
$SUBROUTINES ADVAN6 TOL=5
$MODEL NCOMP=4
COMP=(DEPOT, DEFDOSE)
COMP=(CENTRAL, DEFOBS)
COMP=PERI
COMP=ENZ
$PK
CLI = THETA(1)*EXP(ETA(1))
V2 = THETA(2)*EXP(ETA(2))
Q = THETA(3)
V3 = THETA(4)
EC50 = THETA(5)
KIN = THETA(6)
KOUT = THETA(7)
KA = THETA(8)
EMAX = THETA(9)
ALAG1 = THETA(10)
S2 = V2/1000
K20 = CLI/V2 K23 = Q /V2
K32 = Q /V3
K12=KA
$DES
CP = A(2)/V2
DADT(1)=-KA*A(1)
DADT(2)=-K23*A(2)-K20*A(2)*A(4)+K32*A(3)+KA*A(1)
DADT(3)= - K32* A(3)+ K23*A(2) DADT(4)= KIN*(1+(CP*EMAX/(CP+EC50)))-KOUT*A(4)
$ERROR
IPRED = F
Y=F*EXP(ERR(1))+ERR(2)
ENZY=A(4)
ID DAY DOSE ETIM CONC AMT EVID MDV CMT
102 0 60 0 0 1 1 1 4
102 0 60 0 0 60 1 1 1
102 0 60 0.5 8.17 . 0 0 2
102 0 60 1 39.62 . 0 0 2
102 0 60 1.5 45.43 . 0 0 2
102 0 60 2 55.38 . 0 0 2
102 0 60 3 65.88 . 0 0 2
102 0 60 4 68.21 . 0 0 2
102 0 60 6 47.28 . 0 0 2
102 0 60 8 35.02 . 0 0 2
102 0 60 12 19.26 . 0 0 2
102 0 60 24 7.58 . 0 0 2
102 0 60 48 3.87 . 0 0 2
102 0 60 71.9 2.05 . 0 0 2
102 0 60 72 . 60 1 1 1
102 0 60 84 . 60 1 1 1
102 1 60 95.9 33.11 . 0 0 2
102 1 60 96 . 60 1 1 1
102 1 60 108 . 60 1 1 1
102 2 60 119.9 40.35 . 0 0 2
102 2 60 120 . 60 1 1 1
102 2 60 132 . 60 1 1 1
102 3 60 144 . 60 1 1 1
102 3 60 156 . 60 1 1 1
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The following message was posted to: PharmPK
Hi Shefali,
We published a model on the autoinduction properties of the antimalarial drug, artemisinin a few years ago (Gordi et al. Br J Clin Pharmacol. 2005 Feb;59(2):189-98). The model employs a turn-over concept of an enzyme pool. The latter affects the extraction degree of the drug according to a well-stirred model, affecting both the clearance as well as the bioavailability of the drug. One of the advantages of our proposed model is that the liver compartment is separated from the sampling compartment. Doing so allows the amount of the drug that reaches the liver to affect the enzymes. I believe it is a better way than allowing plasma concentrations of the drug to drive the induction process, as these concentrations fall after repeated dosing (due to induction). The model should also be flexible enough to describe autoinhibition or induction/inhibition of another compound.
Let me know if you need the modeling code (in NONMEM) for the model.
Toufigh
Toufigh Gordi, PhD
Clinical Pharmacology, PK/PD analysis consultant
www.tgordi.com
E-mail: tg.aaa.tgordi.com
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Hi rizwan.aaa.email.unc.edu (sorry, your email does not have your name),
You need to add a stationary condition to your enzyme equation, Kin and Kout are not independent, they are connected through Kin=Kout*BASE, where BASE is amount of enzyme in the compartment when there is no drug. By giving unit dose to enzyme compartment at time 0, you assume that BASE=1. Then, you should have THETA for only one of these 2 parameters, and use equality Kin=Kout for the other.
The maximum amount of enzyme (at infinite concentrations) will be 1+EMAX, so clearance will increase (1+Emax) times. If you want clearance to increase Emax times, then you need to change (CP*EMAX/(CP+EC50)) to (CP*(EMAX-1)/(CP+EC50)).
Also, starting with NONMEM version 6, you no longer need to add a unit dose to the compartment to initialize it, you can do it directly in the control stream.
Regards,
Katya
Ekaterina Gibiansky, Ph.D.
CEO&CSO, QuantPharm LLC
Web: www.quantpharm.com
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Hi Rizwan
You mentioned that your compound is metabolised by 3A4 then perhaps you need to consider auto-induction in the gut too. Time-dependent inhibition (and auto-inhibition) is somehow similar to induction (and auto-induction) and in the following paper a physiologically based model is proposed which accounts for effects of perpetrator and its metabolite in the gut and liver on victim drug.
Rowland Yeo K, Jamei M, Yang J, Tucker GT and Rostami-Hodjegan A (2010) Physiologically-based mechanistic modelling to predict complex drug-drug interactions involving simultaneous competitive and time-dependent enzyme inhibition by parent compound and its metabolite in both liver and gut-the effect of diltiazem on the time-course of exposure to triazolam. European Journal of Pharmaceutical Sciences 39:298-309.
Please note that the gut and liver enzyme turn-over values are different (so you need separate effect models) because in the gut enterocyte turn-over mainly dictates enzymes turn-over.
Also, you mentioned you expect to get Kout around 0.029 1/h; I'm not sure how you get this value but this is more in line with enterocyte turn-over value of around 24 h. However, reported 3A4 turn-over based on in vivo experiments is longer than this (35-100 h), please see:
Yang J, Liao M, Shou M, Jamei M, Yeo KR, Tucker GT and Rostami-Hodjegan A (2008) Cytochrome P450 turnover: regulation of synthesis and degradation, methods for determining rates, and implications for the prediction of drug interactions. Curr Drug Metab 9:384-394.
Almond LM, Yang J, Jamei M, Tucker GT and Rostami-Hodjegan A (2009) Towards a Quantitative Framework for the Prediction of DDIs Arising from Cytochrome P450 Induction. Curr Drug Metab 10:420-432.
Regards
Masoud
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