Re: [NMusers] The double peak

Dear Chenguang,

You wrote: "The ka of the first peak is greater than that of
the second, and the ke of the first is also greater than the second."

You seem to mix absorption and disposition here. I assume
you mean that the plasma concentrations decline faster after the
second peak than after the first. One reason for this observation
would be that the two absorption processes are not of the same
order. I.e. absorption might be more like a first-order process for the
first peak and more like a zero-order process after the second peak.
This might be caused by an absorption window for the 2nd peak.

In your model, you could dose a bolus into the gut compartment
with or without a short lag-time and then you dose a zero order infusion
with a longer lag-time into your central compartment. This should work
and does not require differential equations. ADVAN4 and TRANS3 or 4
will work and will run much faster than the ADVAN6 model you have.

Unless you have a drug which reaches concentrations in the liver
during the absorption which are high enough to inhibit systemic
metabolism, disposition should be independent from the absorption
process.

I would suggest you use your favorite simulation tool and try if you
can generate profiles of the same shape as the ones you are seeing
in your study to find out, if a candidate model may be appropriate.

Hope it helps.

Best regards
Jurgen


-----------------------------------------------
Jurgen Bulitta, PhD, Post-doctoral Fellow
Pharmacometrics, University at Buffalo, NY, USA
Phone: +1 716 645 2855 ext. 281, jbulitta_at_buffalo.edu
-----------------------------------------------



-----Ursprüngliche Nachricht-----
Von: "Chenguang Wang" <maurice.wang_at_gmail.com>
Gesendet: 16.11.07 16:35:45
An: nmusers_at_globomaxnm.com
Betreff: [NMusers] The double peak


Dear Nonmem users,

I am working with a double peaks PK model. I refered to a recent question =
about this topic and tried the double absorption compartment model suggest=
ed by somebody.

 

Howerver, in my real data, the Ka and Ke for each peak are different. The =
ka of the first peak is greater than that of the second, and the ke of the=
 first is also greater than the second. Therefore, the profile has a sharp=
 peak at first, then a flat peak after that. If I use the double absorptio=
n compartment model, it can give me two different Ka, but can't give me tw=
o different Ke in different time.

 

Then I wanted to add a periphal compartment to solve this problem. My idea=
 is after the admin, part of drug(F1) gets into the plasma quickly(Ka1) th=
en quickly goes to the periphal. So there will be a big Kcp (from central =
to periphal). In the same time, drug eliminates to outside from plasma in =
a speed of Ke, which is very small. After a period of time, the drug in pe=
riphal begins to flow back to central in a same speed of Kcp( Kpc=Kcp). Th=
is will retain the drug concentration in the plasma and prevent the fast d=
rop after the second peak in the c-t profile. Also, a sencond part of drug=
(F2) will be absorbed with a slower Ka2 after a proper lag time. Finally, =
the drug will eliminate outside in the speed of Ke, which is very slow.

 

In order to do this, I use lag time between periphal and central. I am not=
 sure if it is permitted by NONMEM, but at least I didn't find error messa=
ge when I did simulation. Also, I don't know if my model can really work a=
s I expected. But when I did the estimation, it crashed.

Would someone have some good idea about this or can tell me if there is an=
y wrong in my script?

 

Thank you in advance!

 

My model is :

 



$DATA ****.csv
$SUBROUTINES ADVAN6 TRANS1 TOL=3
$MODEL NCOMP=4
 COMP=(ABS1)
 COMP=(ABS2)
 COMP=(CENTRAL)
 COMP=(PERI)


$PK
     
     K13 =THETA(1)
     K23 =THETA(2)
     KE =THETA(3)*EXP(ETA(1))
     ALAG2=THETA(4)*EXP(ETA(2))
     F1 = THETA(5)
     F2 = 1- F1
     K34 =THETA(6)*EXP(ETA(3))
     K43 =THETA(7)*EXP(ETA(4))

     ALAG4=THETA(8)*EXP(ETA(5))



$DES
     DADT(1)=-K13*A(1)
     DADT(2)= -K23*A(2)
     DADT(3)= K13*A(1)+K23*A(2)-KE*A(3)-K34*A(3)+K43*A(4)
     DADT(4)= K34*A(3)-K43*A(4)
     
$ERROR IPRED= F
      Y = IPRED * (1+ERR(1)) + ERR(2)

      IRES = DV - F
      IWRES = IRES/IPRED


$THETA 1 FIX ; K13
         0.6 FIX ; K23
         (0.0001,0.001,0.01) ; KE
         (20,40,60) ; ALAG2
         0.7 FIX ; F1
         (0.5,0.75,1) ; K34
         (0.5,0.75,1) ;K43
         (20,40,60) ;ALAG4


$OMEGA
0.2
0.1
0.1
0.1
0.1


$SIGMA
0.1
0.1


$ESTIMATION METHOD=1 PRINT=1 MAXEVAL=9999 NOABORT SIGDIGITS=3 POSTHOC INTE=
RACTION
        MSFO=msfo.outputfile
................


Maurice



Received on Sun Dec 02 2007 - 19:19:58 EST