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PAGE 2010 registration

From: Grevel, Joachim <Joachim.Grevel>
Date: Fri, 15 Jan 2010 07:34:02 -0000

Dear European NMusers,

I am trying to get to the registration page for PAGE 2010 in Berlin. I
cannot access due to....?

This happened only 15 min after registration opened. Can somebody sort
this out?

 

 

Joachim Grevel

Senior Pharmacometrician

_____________________________________________________________________

AstraZeneca R&D Charnwood

Clinical Pharmacology & DMPK, Charnwood

Bakewell Road, Loughborough, Leics., LE11 5RH, England

Tel +44 (0) 1509 644035 Fax +44 (0) 1509 645576 Mobile +44 (0) 7920
285905

joachim.grevel

 

 P Please consider the environment before printing this e-mail

 

 

 

From: owner-nmusers
On Behalf Of M Jamei
Sent: 17 December 2009 03:12
To: prhutson
owner-nmusers
Subject: RE: [NMusers] Duration of Absorption Time From Depot (Gut) as
Covariate

 

Hi Paul

In your first email you mentioned:

... data that suggest a dependence of AUC and Cmax upon transit time in
the gut. The elimination rates for the one compartment model are quite
similar, suggesting that the variability lies in bioavailability.
Preliminary data suggest that the absorption of this drug from the gut
is transporter-limited, and may be dependent upon the duration of time
that the drug is exposed to a specific portion of the duodenum or
jejunum.

Based on these indications, if you manage to obtain reliable predictions
for the Weibull distribution function and the time mapping parameter
[THETA(IVIVC)] these parameters embody a mixture of dissolution
transformation (in vitro to in vivo), interplay of transporters and gut
enzymes, drug permeability in different segments of the gut and the gut
physiology and anatomy e.g. small intestine transit time, duodenum
length, etc. Also the related inter-individual variability values and
covariates may not provide consistent explanation of the observed
variability.

In such cases application of (semi) physiologically-based models
facilitates incorporation of extra information such as any
physicochemical, in vitro or imaging data as well as physiological
knowledge in the model which can give better understanding of the drug
behaviour in the body, please see:

http://www.pkuk.org.uk/ContentImages/KiyohikoSugano.pdf

http://www.pkuk.org.uk/ContentImages/MartinBergstrand.pdf

http://www.pkuk.org.uk/ContentImages/MasoudJamei.pdf.

Regards

Masoud

From: owner-nmusers
On Behalf Of Paul Hutson
Sent: 16 December 2009 21:18
Cc: NMUSERS
Subject: Re: [NMusers] Duration of Absorption Time From Depot (Gut) as
Covariate

Leonid:
Thank you very much for your clear and helpful answer.
May I suggest that the Weibull distribution function might be more
clearly written:
B= IVIVC*PAR1
WDER=(GAMA1/B)*((T/B)**(GAMA1-1))*EXP(-(T/B)**GAMA1)

Be well.
Paul

Leonid Gibiansky wrote:

Paul,
No, this is not a correct way to introduce drug to depot. The idea was:

Step 1. Fit Weibull or something similar to the dissolution data:
time t = 0, 1, 2,...
fraction absorbed: f = 0, 0.1, 0.5 ..
Use model:
f(t)=1-exp(t/to)^gamma
Using observed dissolution data, finds t0 and gamma that would provide
good fit of the dissolution data
If needed, add extra parameter
f(t)=A*(1-exp(t/to)^gamma)

Step 2: Assume some IVIVC model, for example:
in-vivo dissolution is the same as in vitro:
FF=1-exp(t/to)^gamma
or
in-vivo dissolution is faster/slower then in vitro:
FF=1-exp(t/(THETA(IVIVC)*t0))^gamma
where THETA is estimated
or some other model

Step 3:
put drug to depot, but it should be in the $DES block, and it should be
a derivative of FF, not FF itself:

$DES
B=THETA(IVIVC)*t0
WDER=GAMM/(B**GAMM))*T**(GAMM-1)*EXP(-(T/B)**GAMM)

DADT(1)=F1*DOSE*WDER-KA*A(1)

Here t0 and GAMM are fixed (from in-vitro data fit) while THETA(IVIVC)
corresponds to IVIVC and need to be estimated from the data.

If you would like to stop dissolution at some time TMAX, you can use:

$DES
B=THETA(IVIVC)*t0
WDER=GAMM/(B**GAMM))*T**(GAMM-1)*EXP(-(T/B)**GAMM)
IF(T.GT.TMAX) WDER=0
DADT(1)=F1*DOSE*WDER-KA*A(1)

If you would like to stop absorption at some time TMAX, you can use:
$DES
B=THETA()*t0
WDER=GAMM/(B**GAMM))*T**(GAMM-1)*EXP(-(T/B)**GAMM)
IF(T.GT.TMAX) KA=0
DADT(1)=F1*DOSE*WDER-KA*A(1)


Thanks
Leonid

--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com <http://www.quantpharm.com/>
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566




Paul Hutson wrote:

Leonid & Jeroen:
Thank you for your suggestions. I incorporated Jeroen's suggestion of
using MTIME below, with a slight modification (KA = TVKA =
*(1-MPAST(1))),
since I want to turn KA off, not on, at TOFF.

I try below to use Leonid's suggestion of a Weibull distribution to
describe the dissolution of the oral product, rather than using multiple
AMT & RATE inputs corresponding to the dissolution data for the product.
My fit deteriorates both by OBj Func and VPC. Does the code below appear
to be appropriate for introducing the oral drug in A(1) using a Weibull
distribution?
Thanks very much
Paul

$SUBROUTINES ADVAN6 TOL=3
$MODEL COMP=(DEPOT, DEFDOSE) COMP=(CENTRAL, DEFOBS)
$PK
callfl=-2
CL=THETA(1)*EXP(ETA(1)); CLEARANCE
V2=THETA(2)*EXP(ETA(2)); V2
TOFF=THETA(3)*EXP(ETA(3)); DURATION OF PRESENCE IN ABSORPTION SEGMENT
K=CL/V2
AUC=AMT/CL
S2=V2/1000

;CLOSE ABSORPTION AFTER SOME TIME TOFF
TVKA=THETA(4)*EXP(ETA(4))
MTIME(1)=TOFF
KA=TVKA*(1.001-MPAST(1)); MPAST(1) = O UNTIL MTIME(1)(TOFF) IS =
REACHED,
THEN IS 1

;DRUG APPEARANCE
PAR1=THETA(5); SCALING CONSTANT FOR TIME
GAMA1=THETA(6); SLOPE FUNCTION FOR WEIBULL
WB1=1-EXP(-((TIME/PAR1)**GAMA1))
RAT1 = AMT*WB1

$DES
DADT(1) = RAT1 - A(1)*KA
DADT(2) = A(1)*KA - A(2)*CL/V2

$ERROR
IPRE = F
W1=F
DEL = 0
IF(IPRE.LT.0.001) DEL = 1
IRES = DV-IPRE; NEGATIVE TREND IS OVERESTIMATING IPRED WRT DV
IWRE = IRES/(W1+DEL)
Y=F*(1+ERR(1))+ERR(2)


$THETA (0.1,1.23, 50); CL
$THETA (0.10,97.8,1000); V2
$THETA (0.1,86.5,1000); TOFF
$THETA (0.0001, .7, 4); KA
$THETA 176.1 FIXED; PAR1
$THETA 1.033 FIXED ; SLOPE


$OMEGA 0.5; CL
$OMEGA 0.3; V2
$OMEGA 0.6; TOFF
$OMEGA 0.3; ka


$SIGMA .5; SIG1
$SIGMA .1; SIG2

$ESTIMATION METH=1 INT SIGDIGITS=3 MAXEVAL=9999 PRINT=10 NOABORT =


Elassaiss - Schaap, J. (Jeroen) wrote:

Leonid, Paul,

Alternatively one may use the MTIME function in NM6 so the algebraic
solutions in eg. ADVAN2 are still applicable:

$PK
....
MTIME(1)=TOFF
KA=TVKA*MPAST(1)

Best regards,
Jeroen

Jeroen Elassaiss-Schaap, PhD
Modeling & Simulation Expert
Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3)
Early Clinical Research and Experimental Medicine
Schering-Plough Research Institute
T: +31 41266 9320



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-----Original Message-----
From: owner-nmusers

On Behalf Of Leonid Gibiansky
Sent: Friday, 11 December, 2009 6:55
To: prhutson
Cc: NMUSERS
Subject: Re: [NMusers] Duration of Absorption Time From Depot (Gut) as
Covariate

Paul,
You need to rewrite the system using differential equations rather than
ADVAN2 and then use

$DES
FLAG=1
IF(T.GE.TOFF) FLAG=0.0001
KA=TVKA*FLAG

In the PK block, this should not work because your TIME is discrete
while nonmem is trying small variation of TOFF parameter to compute the
gradient (which is indeed zero if you do it in the PK block)

On a different note, you are assuming 1 to 1 IVIVC (in-vitro dissolution

= in vivo dissolution). It is rarely the case. You may try to describe =

your dissolution profile by some function (Weibull is very flexible) and

then use parametric expression for IVIVC (for example, time scaling) to
insert the dose into the depot compartment (as input rate)

Thanks
Leonid



--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com <http://www.quantpharm.com/>
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566




Paul Hutson wrote:

I have been asked to look at data that suggest a dependence of AUC and

 

Cmax upon transit time in the gut. The elimination rates for the one
compartment model are quite similar, suggesting that the variability
lies in bioavailability. Preliminary data suggest that the absorption

 

of this drug from the gut is transporter-limited, and may be dependent

 

upon the duration of time that the drug is exposed to a specific portion
of the duodenum or jejunum. Drug is observed at the earliest sampling
time, so I am not including a Tlag at this point.

I have in vitro dissolution data for this (hopefully) extended release

 

formulation, which I am introducing to the gut compartment for the human
subject PK data as events of AMT and RATE corresponding to each measured
point in the dissolution curve. Thus I am fixing it as a time-dependent
inputs over the 12 hour period following the single dose and during the
plasma sampling. Because of the non-instantaneous

 

input function, I understand I cannot use Savik's TRANSIT model

(2007).

I have tried the code below to try to turn off Ka after some time TOFF,
the point at which the drug is estimated to have moved past the section
of absorption. There is no change in the gradient for TOFF, and the fit
is not improved over a simple 1 compartment absorption

model (ADVAN2).

I cannot turn off compartment 1 (-1) in my INPUT, since I do not know
when to turn it off (I am trying to determine this in the model). There
is extensive first pass of the compound - I do not know of any
auto-inhibition of metabolism. I suppose that I could try to trip F1 to
null at some TOFF, but tripping Ka to Null seems more physiologic.

Can anyone suggest a snippet of code that might close Ka based upon a
covariate THETA corresponding to the time required to move past the
intestinal segment of absorption?
Thanks very much.
Paul

$SUBROUTINES ADVAN2
; 1 COMPARTMENT MODEL, NO LAG, NO LIMIT TO ABSORPTION PERIOD


$PK
TVKA=THETA(1); ABSORPTION RATE FROM GUT CL=THETA(2)*EXP(ETA(1));
CLEARANCE V2=THETA(3)*EXP(ETA(2)); V2 TOFF=THETA(4)*EXP(ETA(3));
DURATION OF PRESENCE IN ABSORPTION SEGMENT
K=CL/V2
DOSE=5; MG TABLET
AUC=DOSE/CL
S2=V2/1000

FLAG=1
IF(TIME.GE.TOFF) FLAG=0.0001
KA=TVKA*FLAG

$ERROR
IPRE = F
W1=F
DEL = 0
IF(IPRE.LT.0.001) DEL = 1
IRES = DV-IPRE; NEGATIVE TREND IS OVERESTIMATING IPRED WRT DV
IWRE = IRES/(W1+DEL)
Y=F*(1+ERR(1))+ERR(2)


$THETA (0.1,1.23, 50); KAGUT
$THETA (0.10,97.8,1000); CL
$THETA (0.1,86.5,1000); V2
$THETA (0.001, 1, 24); DUR


;$OMEGA 0.3; KA
$OMEGA 0.5; CL
$OMEGA 0.3; V2
$OMEGA 0.6; TOFF
--

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



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.


--

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

--

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


Received on Fri Jan 15 2010 - 02:34:02 EST

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