Simple PBPK Model Help- Integration/Convergence Issue

"Vreeland, Ryan *" <[email protected]> Fri, 23 Jun 2017 21:29:32 +0000
Newsgroups gmane.comp.gnu.mcsim
Message-ID <[email protected]>
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Hello,

I have been having trouble the last few days with my PBPK model. I've been =
running a .sim file. The error that keeps popping up is

Doing analysis - 1 normal experiment
 1lsodes-- at current t (=3Dr1), mxstep (=3Di1) steps
         taken on this call before reaching tout
 in above message, i1=3D       500
in above message, r1=3D      0.1039293261229
Warning: Integration failed - No output generated

I have simplified my model down to two compartments to try and figure this =
error out. A colleague and I kept looking over the code to see if there is =
anything wrong, but we do not see anything wrong.  Some observations I have=
 made when attempting to figure this out is, using smaller doses, or differ=
ent body weight seems to help and allow the variables to print to 24 hours.=
  I have also tried changing the tolerances on the integration function, se=
emed to help in some cases. One thing that bugs me, I have been using Print=
Step to print out the variables, and for the same tolerances, bodyweight, a=
nd dose, using a <time-step> of 1 throws the error, while using 0.1 or 0.01=
 works just fine. I had thought that <time-step> is only for telling what t=
ime the system prints out the variables.
I feel like it is being really finicky about converging with certain number=
s, maybe it can't use very big numbers.
I am hoping someone has seen this error before and or can help me figure ou=
t what is wrong with the file. Thank you all for your time.

Here is my model file.

#--------------------------------------------------------------------------=
----
# RA Vreeland - 2017 - US FDA /NCTR
# PBPK model of nitrate and nitrite in humans
# Compartments for nitrate : plasma, thyroid in diffusion limited, rest of =
body, saliva, GI tract(not including large intestines)
# Compartment for nitrite: plasma, saliva, GI, rest of body
#--------------------------------------------------------------------------=
----
#
#
# n =3D nitrate, rf =3D nitrite ('reduced form'); g =3D (stomach, liver, sm=
all intestines)
# s =3D saliva; t =3D thyroid; a =3D arterial; v =3D venus; Hb =3D hemoglob=
in; metHb =3D methemoglobin
# rob =3D rest of body;
#
# As far as I can tell, the model is working, and its a software limiting t=
hing

States =3D {Aplasma_n, Arob_n, AIVD_n};

Outputs =3D {Cn_a, Cnv_total, Cn_rob, Cnv_rob, TestPrint, time};

Inputs =3D {BW, IV_n_g, IVDose_n};


      MW_n;                   # g/mol or mg/mmol
      t_len;
      IV_n_mol;               # mol
      DosePerHour;
      P_nrob;

      volF_plasma;
      volF_rob_n;

      vol_plasma;
      vol_rob_n;

      Q_cardiac;
      Q_rob_n;

      QF_cardiac;
      QF_rob_n;

Initialize {

      MW_n =3D 62.004;                          # g/mol or mg/mmol
      t_len =3D 1.0;
      IV_n_mol =3D IV_n_g/MW_n;             # g * (mol/g)
      DosePerHour =3D IV_n_mol/t_len;

      P_nrob =3D 1.0;

      volF_plasma =3D 0.044;
      volF_rob_n =3D 0.956;

      vol_plasma =3D volF_plasma * BW;
      vol_rob_n =3D volF_rob_n * BW;


      QF_cardiac =3D 15.0;
      QF_rob_n =3D 1.0;                     # 1 - (sum of other non plasma =
compartments) --> only rob compartment currently

      Q_cardiac =3D QF_cardiac * pow(BW, 0.75);
      Q_rob_n =3D QF_rob_n * Q_cardiac;

      }; # End Initialize
Dynamics {

      Cn_a =3D Aplasma_n/vol_plasma;
      Cn_rob =3D Arob_n/vol_rob_n;

# Dose #
      dt(AIVD_n) =3D IVDose_n;
      TestPrint =3D dt(AIVD_n);

# Plasma #

      dt(Aplasma_n) =3D Q_cardiac * (Cnv_total -Cn_a ) + (dt(AIVD_n));
    dt(Arob_n) =3D Q_rob_n * (Cn_a - Cnv_rob);

    Cnv_total =3D (Q_rob_n * Cnv_rob)/Q_cardiac ;
      Cnv_rob =3D Arob_n/(vol_rob_n*P_nrob);


      time =3D t;
}; # End Dynamics

End

This is the output file for reference

OutputFile("NuclearOption.out");
  Integrate(Lsodes, 1e-6, 1e-12, 1);
  #Integrate(Lsodes, 1e-5, 1e-7, 1); #default settings of integration

 # 3 mg/kg dose with Wagners study. Not even close to that, right now

Simulation {
      IV_n_g =3D 0.06196;  # So doing 61.96 dose with BW 75 kg and 1e-6, 1e=
-12, 1 ; print step of 0.1
      IVDose_n =3D PerDose(DosePerHour, 24.0, 0, 1);
      BW =3D 75.0;
      # Seems like the time on the PrintStep step is when each of the calcu=
lations occur, not just when it prints out
      # Well, using print, and 60 mg dose with 1e-6, 1e-12 causes it to fai=
l, but using print step with printing every 0.1 steps it works, go bloody f=
igure

      PrintStep(IVDose_n, AIVD_n, TestPrint, Cn_a, Cnv_total, Cn_rob, Cnv_r=
ob, Arob_n, Aplasma_n, 0.0, 24.0, 0.1 );
      #PrintStep( time, 0.0, 24, 1);

    }

END



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<p class=3D"MsoNormal">Hello, <o:p></o:p></p>
<p class=3D"MsoNormal"><o:p>&nbsp;</o:p></p>
<p class=3D"MsoNormal">I have been having trouble the last few days with my=
 PBPK model. I&#8217;ve been running a .sim file. The error that keeps popp=
ing up is
<o:p></o:p></p>
<p class=3D"MsoNormal"><o:p>&nbsp;</o:p></p>
<p class=3D"MsoNormal">Doing analysis - 1 normal experiment <o:p></o:p></p>
<p class=3D"MsoNormal">&nbsp;1lsodes-- at current t (=3Dr1), mxstep (=3Di1)=
 steps&nbsp;&nbsp; <o:p></o:p></p>
<p class=3D"MsoNormal">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;taken on this call before reaching tout&nbsp;&nbsp;&nbsp;&nbsp; <o:p></o:=
p></p>
<p class=3D"MsoNormal">&nbsp;in above message, i1=3D&nbsp;&nbsp;&nbsp;&nbsp=
;&nbsp;&nbsp; 500<o:p></o:p></p>
<p class=3D"MsoNormal">in above message, r1=3D&nbsp;&nbsp;&nbsp;&nbsp;&nbsp=
; 0.1039293261229<o:p></o:p></p>
<p class=3D"MsoNormal">Warning: Integration failed - No output generated<o:=
p></o:p></p>
<p class=3D"MsoNormal"><o:p>&nbsp;</o:p></p>
<p class=3D"MsoNormal">I have simplified my model down to two compartments =
to try and figure this error out. A colleague and I kept looking over the c=
ode to see if there is anything wrong, but we do not see anything wrong. &n=
bsp;Some observations I have made when
 attempting to figure this out is, using smaller doses, or different body w=
eight seems to help and allow the variables to print to 24 hours. &nbsp;I h=
ave also tried changing the tolerances on the integration function, seemed =
to help in some cases. One thing that
 bugs me, I have been using PrintStep to print out the variables, and for t=
he same tolerances, bodyweight, and dose, using a &lt;time-step&gt; of 1 th=
rows the error, while using 0.1 or 0.01 works just fine. I had thought that=
 &lt;time-step&gt; is only for telling what
 time the system prints out the variables. &nbsp;<o:p></o:p></p>
<p class=3D"MsoNormal">I feel like it is being really finicky about converg=
ing with certain numbers, maybe it can&#8217;t use very big numbers.
<o:p></o:p></p>
<p class=3D"MsoNormal">I am hoping someone has seen this error before and o=
r can help me figure out what is wrong with the file. Thank you all for you=
r time.<o:p></o:p></p>
<p class=3D"MsoNormal"><o:p>&nbsp;</o:p></p>
<p class=3D"MsoNormal">Here is my model file.<o:p></o:p></p>
<p class=3D"MsoNormal"><o:p>&nbsp;</o:p></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">#---------------------------=
---------------------------------------------------<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"># RA
<u><span style=3D"color:black">Vreeland</span></u> - 2017 - US FDA /NCTR<o:=
p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"># PBPK model of
<u><span style=3D"color:black">nitrate</span></u> and <u><span style=3D"col=
or:black">nitrite</span></u> in humans<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"># Compartments for
<u><span style=3D"color:black">nitrate</span></u> : plasma, <u><span style=
=3D"color:black">thyroid</span></u> in diffusion limited, rest of body, sal=
iva, GI tract(not including large intestines)<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"># Compartment for
<u><span style=3D"color:black">nitrite</span></u>: plasma, saliva, GI, rest=
 of body<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">#---------------------------=
---------------------------------------------------<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">#<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">#<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"># n =3D
<u><span style=3D"color:black">nitrate</span></u>, <u><span style=3D"color:=
black">rf</span></u> =3D
<u><span style=3D"color:black">nitrite</span></u> ('reduced form'); g =3D (=
stomach, liver, small intestines)<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"># s =3D saliva; t =3D
<u><span style=3D"color:black">thyroid</span></u>; a =3D arterial; v =3D <u=
><span style=3D"color:black">venus</span></u>;
<u><span style=3D"color:black">Hb</span></u> =3D <u><span style=3D"color:bl=
ack">hemoglobin</span></u>; metHb =3D
<u><span style=3D"color:black">methemoglobin</span></u><o:p></o:p></span></=
p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"># rob =3D rest of body;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">#<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"># As far as I can tell, the =
model is working, and its a software limiting thing<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p>&nbsp;</o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">States =3D {Aplasma_n, Arob_=
n, AIVD_n};<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p>&nbsp;</o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">Outputs =3D {Cn_a, Cnv_total=
, Cn_rob, Cnv_rob, TestPrint, time};<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p>&nbsp;</o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">Inputs =3D {BW, IV_n_g, IVDo=
se_n};<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p>&nbsp;</o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p>&nbsp;</o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; MW_n;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&=
nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; # g/<u><span style=3D"color:black=
">mol</span></u> or
<u><span style=3D"color:black">mg</span></u>/<u><span style=3D"color:black"=
>mmol</span></u><o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; t_len;<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; IV_n_mol;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp; #
<u><span style=3D"color:black">mol</span></u><o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; DosePerHour;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; P_nrob;<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; volF_plasma;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; volF_rob_n;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; vol_plasma;<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; vol_rob_n;<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; Q_cardiac;<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; Q_rob_n;<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; QF_cardiac;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&=
nbsp;&nbsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; QF_rob_n;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p>&nbsp;</o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">Initialize {<o:p></o:p></spa=
n></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p>&nbsp;</o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; MW_n =3D 62.004;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&n=
bsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbs=
p;&nbsp;&nbsp; # g/<u><span style=3D"color:black">mol</span></u> or
<u><span style=3D"color:black">mg</span></u>/<u><span style=3D"color:black"=
>mmol</span></u><o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; t_len =3D 1.0;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; IV_n_mol =3D IV_n_g/MW_n;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp=
;&nbsp;&nbsp;&nbsp;&nbsp; # g * (<u><span style=3D"color:black">mol</span><=
/u>/g)
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; DosePerHour =3D IV_n_mol/t_len;<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; P_nrob =3D 1.0;<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; volF_plasma =3D 0.044;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&n=
bsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; volF_rob_n =3D 0.956; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&n=
bsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; vol_plasma =3D volF_plasma * BW;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;&nbsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; vol_rob_n =3D volF_rob_n * BW;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p>&nbsp;</o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; QF_cardiac =3D 15.0;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; QF_rob_n =3D 1.0;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&=
nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; # 1 - (su=
m of other non plasma compartments) --&gt; only rob compartment currently<o=
:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; Q_cardiac =3D QF_cardiac *
<u><span style=3D"color:black">pow</span></u>(BW, 0.75);<o:p></o:p></span><=
/p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; Q_rob_n =3D QF_rob_n * Q_cardiac;&nbsp;&nbsp;&nbsp;&nbsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; }; # End Initialize<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">Dynamics {<o:p></o:p></span>=
</p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p>&nbsp;</o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; Cn_a =3D Aplasma_n/vol_plasma;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; Cn_rob =3D Arob_n/vol_rob_n;<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"># Dose #<o:p></o:p></span></=
p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<u><span style=3D"color:black">dt</span></u>(AIVD_n) =3D IVDose_n;<o:p></o:=
p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; TestPrint =3D
<u><span style=3D"color:black">dt</span></u>(AIVD_n);<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"># Plasma #&nbsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<u><span style=3D"color:black">dt</span></u>(Aplasma_n) =3D Q_cardiac * (Cn=
v_total -Cn_a ) &#43; (<u><span style=3D"color:black">dt</span></u>(AIVD_n)=
);&nbsp;&nbsp;&nbsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;
<u><span style=3D"color:black">dt</span></u>(Arob_n) =3D Q_rob_n * (Cn_a - =
Cnv_rob);<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;Cnv_=
total =3D (Q_rob_n * Cnv_rob)/Q_cardiac ;<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; Cnv_rob =3D Arob_n/(vol_rob_n*P_nrob);<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; time =3D t;<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">}; # End Dynamics<o:p></o:p>=
</span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p>&nbsp;</o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">End<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p>&nbsp;</o:p></span></p>
<p class=3D"MsoNormal">This is the output file for reference<o:p></o:p></p>
<p class=3D"MsoNormal"><o:p>&nbsp;</o:p></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">OutputFile(&quot;NuclearOpti=
on.out&quot;);<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp; Integrate(<u><span st=
yle=3D"color:black">Lsodes</span></u>, 1e-6, 1e-12, 1);<o:p></o:p></span></=
p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp; #Integrate(<u><span s=
tyle=3D"color:black">Lsodes</span></u>, 1e-5, 1e-7, 1); #default settings o=
f integration<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;<o:p></o:p></spa=
n></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;# 3
<u><span style=3D"color:black">mg</span></u>/<u><span style=3D"color:black"=
>kg</span></u> dose with
<u><span style=3D"color:black">Wagners</span></u> study. Not even close to =
that, right now<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p>&nbsp;</o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">Simulation {<o:p></o:p></spa=
n></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; IV_n_g =3D 0.06196;&nbsp; # So doing 61.96 dose with BW 75
<u><span style=3D"color:black">kg</span></u> and 1e-6, 1e-12, 1 ; print ste=
p of 0.1
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; IVDose_n =3D PerDose(DosePerHour, 24.0, 0, 1);&nbsp;&nbsp;&nbsp;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; BW =3D 75.0;<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; # Seems like the time on the PrintStep step is when each of the calculat=
ions occur, not just when it prints out<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; # Well, using print, and 60
<u><span style=3D"color:black">mg</span></u> dose with 1e-6, 1e-12 causes i=
t to fail, but using print step with printing every 0.1 steps it works, go =
bloody figure<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; PrintStep(IVDose_n, AIVD_n, TestPrint, Cn_a, Cnv_total, Cn_rob, Cnv_rob,=
 Arob_n, Aplasma_n, 0.0, 24.0, 0.1 );<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p; #PrintStep( time, 0.0, 24, 1);<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp;&nbsp;&nbs=
p;
<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">&nbsp;&nbsp;&nbsp; }<o:p></o=
:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p>&nbsp;</o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;">END<o:p></o:p></span></p>
<p class=3D"MsoNormal" style=3D"text-autospace:none"><span style=3D"font-si=
ze:10.0pt;font-family:&quot;Courier New&quot;"><o:p>&nbsp;</o:p></span></p>
<p class=3D"MsoNormal"><o:p>&nbsp;</o:p></p>
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