Dear All,
I am looking for a help. Currently I am working on a population PD model to evaluate the effects of drugs on QT prolongation. Drug A and drug B are given to the study subjects (healthy volunteer) at the same time. Drug B is the inhibitor for the metabolism of drug A, also compound C is the metabolite of drug A. I am wondering how to evaluate the effects for drug A or B or the metabolite of drug A (compound C). These three moieties will be present together in the blood for most of the time. Is anyone has experience and would like to share with us. Any comment will be greatly appreciated.
Best regards,
Yuhong
____________________________________________________________
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PD model
Dear All,
I am looking for a help. Currently I am working on a population PD model to
evaluate the effects of drugs on QT prolongation. Drug A and drug B are given
to the study subjects (healthy volunteer) at the same time. Drug B is the
inhibitor for the metabolism of drug A, also compound C is the metabolite of
drug A. I am wondering how to evaluate the effects for drug A or B or the
metabolite of drug A (compound C). These three moieties will be present
together in the blood for most of the time. Is anyone has experience and would
like to share with us. Any comment will be greatly appreciated.
Best regards,
Yuhong
____________________________________________________________
Diet Help
Reach your goals of being healthier and happier. Click here for diet tips and
solutions.
http://thirdpartyoffers.netzero.net/TGL2241/c?cp=0TyE90NYD1UWB77GnvM8cgAAJ1EqI3_TpApLLwjS4plsTl0gAAYAAAAAAAAAAAAAAAAAAADNAAAAAAAAAAAAAAAAAAAYQAAAAAA=
Dear Otilia,
Thank you very much for your suggestions. They are very helpful.
Thanks,
Yuhong
Quoted reply history
---------- Original Message ----------
From: Lillin - de Vries, O. - <otilia.lillin
To: <chenyuhong
Subject: RE: [NMusers] PD model
Date: Thu, 14 Jan 2010 11:45:16 +0100
Dear Yuhong, Here you have my 5 cents (in top-down fashion): 1. You need a PK-PD model quantifying the QTc prolongation; since you don't know what causes the QTc prolongation, this breaks down to testing: 1a. DrugA - QTc model 1b. DrugB - QTc model 1c. DrugA+DrugB - QTc model 1d. DrugC - QTc model In order to be able to compare models 1a - 1d you need a good Baseline QTc model (i.e you need to describe well all non-drug related influences on QTc like gender, circadian rhythm, age, placebo effect, etc - see e.g. the paper of V. Piotrovsky, Pharmacokinetic-Pharmacodynamic Modeling in the Data Analysis and Interpretation of Drug-induced QT/QTc Prolongation, AAPS Journal 2005). If a combination of more than one of your three moieties can be responsible for the effect on QTc (I do not have experience with this case) I would simply add upp the concentrations (see the Nonmem code below for your convenience, without circadian rhythm for keeping it simple). On the other hand be aware that a PK-PD model can not tell you for sure which one of the moieties is responsible for the QTc prolongation; a model can only quantify the magnitude of the effect and give you a hint on which moiety is most probably causing it. You need to make assumptions on physiological bases as well, and:- check whether drugB alone causes QTc prolongation (model 1b? litterature? previous studies with limited ECG? ...) if yes, you need model 1c.- check the time point at which you have the largest QTc prolongation: does it occur at Tmax_drugA? then a direct effect model (1a or 1c) are most probable; does it occur at Tmax_drugC? since C is a metabolite, it takes some time to be formed and probably Tmax_C > Tmax_A, this hints you in the direction of the metabolite and you need a delayed effect model to describe the parent's effect on QTc (1a) and the concentrations in the hypothetical compartment should agree with the metabolite profile. In other words, you should be able to tell the effect from the parent(s) and metabolite from each other. Hope this helps. Cheers,Otilia $PREDOCC2=0 ; steady state IF (DAY.EQ.11) OCC2=1 QTC0 = THETA(1)+ETA(1) ;baseline QTcSHFT = THETA(2) ;shift factor placebo effect QTCB = QTC0+SHFT*OCC2+THETA(3)*GEN ;baseline with placebo and gender effect SL = THETA(4) ; slope of drug effectCP = CA + CB ; add upp concentrations causing the effectEFF = SL*CP ; linear direct effect QTC = QTCB+EFF Y =
QTC+EPS(1)IPRE = QTCIRES = DV-IPRE Otilia Lillin-de Vries, MSc
Modeling and Simulation Expert
Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3)
Department of Drug Metabolism and Pharmacokinetics
T: +31 412 669321
M: + 31 6 22004827
F: +31 412 662506
otilia.lillin
MSD
Gasstraat Oost 10, 5349 AV, Oss
P.O. Box 20, 5340 BH, Oss
The Netherlands
www.merck.com
From: owner-nmusers
On Behalf Of chenyuhong
Sent: Thursday, 14 January, 2010 2:45
To: nmusers
Subject: [NMusers] PD model
Dear All,
I am looking for a help. Currently I am working on a population PD model to evaluate the effects of drugs on QT prolongation. Drug A and drug B are given to the study subjects (healthy volunteer) at the same time. Drug B is the inhibitor for the metabolism of drug A, also compound C is the metabolite of drug A. I am wondering how to evaluate the effects for drug A or B or the metabolite of drug A (compound C). These three moieties will be present together in the blood for most of the time. Is anyone has experience and would like to share with us. Any comment will be greatly appreciated.
Best regards,
Yuhong
____________________________________________________________
Diet Help
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This message and any attachments are solely for the intended recipient. If you are not the intended recipient, disclosure, copying, use or distribution of the information included in this message is prohibited --- Please immediately and permanently delete.
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Title: Paul R
Yuhong:
Otilia makes useful recommendations, and I would just reinforce the
caution of having a good baseline and an understanding of the
individual's diurnal changes. There is increasingly recognized to be a
very large natural variability in QTc that will need to be considered.
Daily swings of 90msec are apparently not uncommon when 24 hr
recordings are made in normal adults.
Paul
[email protected] wrote:
Dear Otilia,
Thank you very much for your suggestions. They are very helpful.
Thanks,
Yuhong
Quoted reply history
---------- Original Message ----------
From: "Lillin - de Vries, O. \(Otilia\)"
< [email protected] >
To: < [email protected] > , < [email protected] >
Subject: RE: [NMusers] PD model
Date: Thu, 14 Jan 2010 11:45:16 +0100
Dear Yuhong,
Here you have my 5 cents (in
top-down fashion):
1. You need a PK-PD model
quantifying the QTc prolongation; since you don't know what causes the
QTc prolongation, this breaks down to testing:
1a. DrugA - QTc model
1b. DrugB - QTc model
1c. DrugA+DrugB - QTc
model
1d. DrugC - QTc model
In order
to be able to compare models 1a - 1d you need a good Baseline QTc model
(i.e you need to describe well all non-drug related influences on QTc
like gender, circadian rhythm, age, placebo effect, etc - see e.g. the
paper of V. Piotrovsky, Pharmacokinetic-Pharmacodynamic
Modeling in the Data Analysis and Interpretation
of Drug-induced QT/QTc Prolongation, AAPS Journal 2005 ).
If a combination of more
than one of your three moieties can be responsible for the effect on
QTc (I do not have experience with this case) I would simply add upp
the concentrations (see the Nonmem code below for your convenience,
without circadian rhythm for keeping it simple).
On the other hand be aware
that a PK-PD model can not tell you for sure which one of the moieties
is responsible for the QTc prolongation; a model can only quantify the
magnitude of the effect and give you a hint on which moiety is most
probably causing it.
You need to make assumptions
on physiological bases as well, and:
- check whether drugB
alone causes QTc prolongation (model 1b? litterature? previous studies
with limited ECG? ...) if yes, you need model 1c.
- check the time point at
which you have the largest QTc prolongation: does it occur at
Tmax_drugA? then a direct effect model (1a or 1c) are most probable;
does it occur at Tmax_drugC? since C is a metabolite, it takes some
time to be formed and probably Tmax_C > Tmax_A, this hints you in
the direction of the metabolite and you need a delayed effect model to
describe the parent's effect on QTc (1a) and the concentrations in the
hypothetical compartment should agree with the metabolite profile. In
other words, you should be able to tell the effect from the
parent(s) and metabolite from each other.
Hope this helps.
Cheers,
Otilia
$PRED
OCC2=0
; steady state
IF
(DAY.EQ.11) OCC2=1
QTC0
= THETA(1)+ETA(1 ) ;baseline QTc
SHFT =
THETA(2) ;shift
factor placebo effect
QTCB
= QTC0+SHFT*OCC2+THETA(3)*GEN ;baseline
with placebo and gender effect
SL =
THETA(4)
; slope of drug effect
CP = CA +
CB ; add upp
concentrations causing the effect
EFF =
SL*CP
; linear direct effect
QTC =
QTCB+EFF
Y =
QTC+EPS(1)
IPRE = QTC
IRES =
DV-IPRE
Otilia Lillin-de Vries, MSc
Modeling
and Simulation Expert
Pharmacokinetics,
Pharmacodynamics & Pharmacometrics (P3)
Department of Drug
Metabolism and Pharmacokinetics
T: +31 412 669321
M: + 31 6 22004827
F: +31 412 662506
[email protected]
MSD
Gasstraat Oost 10, 5349 AV, Oss
P.O.
Box 20, 5340 BH, Oss
The
Netherlands
www.merck.com
From:
[email protected] [ mailto: [email protected] ] On
Behalf Of [email protected]
Sent: Thursday, 14 January, 2010 2:45
To: [email protected]
Subject: [NMusers] PD model
Dear All,
I am looking for a help. Currently I am working on a population
PD model to evaluate the effects of drugs on QT prolongation. Drug A
and drug B are given to the study subjects (healthy volunteer) at the
same time. Drug B is the inhibitor for the metabolism of drug A,
also compound C is the metabolite of drug A. I am wondering how to
evaluate the effects for drug A or B or the metabolite of drug A
(compound C). These three moieties will be present together in the
blood for most of the time. Is anyone has experience and would like to
share with us. Any comment will be greatly appreciated.
Best regards,
Yuhong
____________________________________________________________
Diet Help
Reach your goals of being healthier and happier. Click here for diet
tips and solutions.
This message and any attachments are solely for the intended
recipient. If you are not the intended recipient, disclosure, copying,
use or distribution of the information included in this message is
prohibited --- Please immediately and permanently delete.
____________________________________________________________
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Paul R.
Hutson, Pharm.D.
Associate
Professor
UW School
of Pharmacy
777
Highland Avenue
Madison
WI 53705-2222
Tel 608.263.2496
Fax
608.265.5421
Pager
608.265.7000, p7856
Here are my thoughts on this topic and the models:
I agree with the comments made about the baseline and the method to deal with
estimating the baseline pattern of QTc.
But, adding up concentrations of two different drugs should be the last resort,
because it assumes that the drugs are equipotent (with respect to causing QT
prolongation) and that they follow the same underlying shape of PK-QT
relationship. This is an assumption that could be rarely the case in real life.
I would first try a different model. What needs to be added up is the PD (i.e.,
QT prolongation) not the concentrations. If the individual PK-QT relationships
for Drugs A, B and the metabolite C are sufficiently separated (i.e., different
half-lives for the three compounds and have different PK-QT slopes or different
EC50 and Emax values in the case of an Emax model), then you could try to fit a
model like:
EFFA = SLA*CPA ;Effect of drug A=SlopeA x Plasma concentrations of
drug A
EFFB= SLB*CPB ;Similar to above for drug B
EFFC= SLC*CPC ;Similar to above for metabolite C
EFF=EFFA+EFFB+EFFC ;Total drugs effect on QT
QTC = QTC0+EFF ;QTC0 is the baseline QTc effect (could be a
diurnal variation model, etc)
Of course, the model requires enough data points and works if there is enough
separation between the slopes of the PK-QT effects. If the above model does
not fit, I would next use the pre-clinical data (e.g., hERG test) to eliminate
at least one of the moieties for potential QT prolongation and that should
simplify the model.
Regards
Parviz Ghahramani, PhD, PharmD, MSc, MBA
Executive Director, Clinical Pharmacology and Drug Dynamics
Forest Research Institute
A Subsidiary of Forest Research Laboratories, Inc.
Harborside Financial Center, Plaza V
Jersey City, NJ 07311
201-427-8469 (office)
917- 828-3836 (cell)
201-427-8498 (fax)
[email protected]
Date: Thu, 14 Jan 2010 09:24:15 -0600
From: [email protected]
Subject: Re: [NMusers] PD model
CC: [email protected]
Yuhong:
Otilia makes useful recommendations, and I would just reinforce the caution of
having a good baseline and an understanding of the individual's diurnal
changes. There is increasingly recognized to be a very large natural
variability in QTc that will need to be considered. Daily swings of 90msec are
apparently not uncommon when 24 hr recordings are made in normal adults.
Paul
[email protected] wrote:
Dear Otilia,
Thank you very much for your suggestions. They are very helpful.
Thanks,
Yuhong
Quoted reply history
---------- Original Message ----------
From: "Lillin - de Vries, O. \(Otilia\)" <[email protected]>
To: <[email protected]>, <[email protected]>
Subject: RE: [NMusers] PD model
Date: Thu, 14 Jan 2010 11:45:16 +0100
Dear Yuhong,
Here you have my 5 cents (in top-down fashion):
1. You need a PK-PD model quantifying the QTc prolongation; since you don't
know what causes the QTc prolongation, this breaks down to testing:
1a. DrugA - QTc model
1b. DrugB - QTc model
1c. DrugA+DrugB - QTc model
1d. DrugC - QTc model
In order to be able to compare models 1a - 1d you need a good Baseline QTc
model (i.e you need to describe well all non-drug related influences on QTc
like gender, circadian rhythm, age, placebo effect, etc - see e.g. the paper of
V. Piotrovsky, Pharmacokinetic-Pharmacodynamic Modeling in the Data Analysis
and Interpretation of Drug-induced QT/QTc Prolongation, AAPS Journal 2005).
If a combination of more than one of your three moieties can be responsible for
the effect on QTc (I do not have experience with this case) I would simply add
upp the concentrations (see the Nonmem code below for your convenience, without
circadian rhythm for keeping it simple).
On the other hand be aware that a PK-PD model can not tell you for sure which
one of the moieties is responsible for the QTc prolongation; a model can only
quantify the magnitude of the effect and give you a hint on which moiety is
most probably causing it.
You need to make assumptions on physiological bases as well, and:
- check whether drugB alone causes QTc prolongation (model 1b? litterature?
previous studies with limited ECG? ...) if yes, you need model 1c.
- check the time point at which you have the largest QTc prolongation: does it
occur at Tmax_drugA? then a direct effect model (1a or 1c) are most probable;
does it occur at Tmax_drugC? since C is a metabolite, it takes some time to be
formed and probably Tmax_C > Tmax_A, this hints you in the direction of the
metabolite and you need a delayed effect model to describe the parent's effect
on QTc (1a) and the concentrations in the hypothetical compartment should agree
with the metabolite profile. In other words, you should be able to tell the
effect from the parent(s) and metabolite from each other.
Hope this helps.
Cheers,
Otilia
$PRED
OCC2=0 ; steady state
IF (DAY.EQ.11) OCC2=1
QTC0 = THETA(1)+ETA(1) ;baseline QTc
SHFT = THETA(2) ;shift factor
placebo effect
QTCB = QTC0+SHFT*OCC2+THETA(3)*GEN ;baseline with placebo and gender effect
SL = THETA(4) ; slope of drug
effect
CP = CA + CB ; add upp
concentrations causing the effect
EFF = SL*CP ; linear direct
effect
QTC = QTCB+EFF
Y = QTC+EPS(1)
IPRE = QTC
IRES = DV-IPRE
Otilia Lillin-de Vries, MSc
Modeling and Simulation Expert
Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3)
Department of Drug Metabolism and Pharmacokinetics
T: +31 412 669321
M: + 31 6 22004827
F: +31 412 662506
[email protected]
MSD
Gasstraat Oost 10, 5349 AV, Oss
P.O. Box 20, 5340 BH, Oss
The Netherlands
www.merck.com
From: [email protected] [mailto:[email protected]] On
Behalf Of [email protected]
Sent: Thursday, 14 January, 2010 2:45
To: [email protected]
Subject: [NMusers] PD model
Dear All,
I am looking for a help. Currently I am working on a population PD model to
evaluate the effects of drugs on QT prolongation. Drug A and drug B are given
to the study subjects (healthy volunteer) at the same time. Drug B is the
inhibitor for the metabolism of drug A, also compound C is the metabolite of
drug A. I am wondering how to evaluate the effects for drug A or B or the
metabolite of drug A (compound C). These three moieties will be present
together in the blood for most of the time. Is anyone has experience and would
like to share with us. Any comment will be greatly appreciated.
Best regards,
Yuhong
____________________________________________________________
Diet Help
Reach your goals of being healthier and happier. Click here for diet tips and
solutions.
This message and any attachments are solely for the intended recipient. If you
are not the intended recipient, disclosure, copying, use or distribution of the
information included in this message is prohibited --- Please immediately and
permanently delete.
____________________________________________________________
Weight Loss Program
Best Weight Loss Program - Click Here!
--
Paul R. Hutson, Pharm.D.
Associate Professor
UW School of Pharmacy
777 Highland Avenue
Madison WI 53705-2222
Tel 608.263.2496
Fax 608.265.5421
Pager 608.265.7000, p7856
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