Re: [NMusers] Time-Varying Bioavailability on Zero-Order Infusion

From: Leonid Gibiansky <lgibiansky_at_quantpharm.com>
Date: Tue, 13 Mar 2018 22:41:22 -0400

Hi Bill,

Interesting problem...
Bioavailability + dose are implemented as initial conditions (for bolus)
or constant term in equations (for infusion). It is very difficult if
not impossible to implement general time-dependent right-hand side with
the user interface simpler than what you are using now (that is, define
RATEIN as a function of time).
Best!
Leonid


On 3/13/2018 10:08 PM, Bill Denney wrote:
> Hi Leonid,
>
> The biology behind it is that during a long (many day) infusion, there
> appears to be adsorption to the infusion tubing and/or catheter. The real
> model I'm developing is more complex in the adsorption part (there may be
> saturable adsorption as shown with the dynamics in the first days), and I
> want it to be accurate as a continuous time variant IV bioavailability
> because I'm trying to predict different infusion rates and durations.
>
> The model mis-fit is both a dose-related apparent bioavailability change
> (much simpler to implement than what is here) and a dose- and time-related
> apparent change in bioavailability during the first portion of the dosing
> due to the potential saturation of the adsorption. The kinetics after the
> end of the infusion all appear to be linear over a moderate-to-large dose
> range, so I don't think that it's more complex human biology.
>
> And for the current data set, the model runs quickly (it isn't that I'm
> having to sit around forever for the solution). The technical question was
> if there was some part of NONMEM that I didn't know related to controlling
> infusion rates in the $DES block. (Feature request to Bob and Alison: Maybe
> in NONMEM 7.5, the user could set R1 = -1 in $PK and have continuous control
> of R1 in $DES-- generalized to include all compartments.)
>
> Thanks,
>
> Bill
>
> -----Original Message-----
> From: Leonid Gibiansky <lgibiansky_at_quantpharm.com>
> Sent: Tuesday, March 13, 2018 9:34 PM
> To: Sebastien Bihorel <sebastien.bihorel_at_cognigencorp.com>; Bill Denney
> <wdenney_at_humanpredictions.com>
> Cc: NMUsers <nmusers_at_globomaxnm.com>
> Subject: Re: [NMusers] Time-Varying Bioavailability on Zero-Order Infusion
>
> Hi Bill,
>
> I think the proposed original solution is the only one if you would like to
> implement it exactly. May be it can be approximated somehow? What is the
> real reason for this questions? What is the biology behind the time-variant
> IV bioavailability? Or what is the model mis-fit that you are trying to fix?
>
> Leonid
>
>
>
>
> On 3/13/2018 9:16 PM, Sebastien Bihorel wrote:
>> Hi,
>>
>> I would suggest the following solution which should also work if you
>> want to apply some covariate effect on bioavailability:
>> * On the dataset side, set your RATE variable to -1 and store the
>> actual infusion rates into another variable, eg IVRATE
>> * On the model side:
>> $PK
>> ...
>>
>> ; assuming the IV infusion are made in compartment 1
>> F1 = <whatever time varying function>
>> R1 = F1*IVRATE
>>
>> Voila, NONMEM should take care of the dosing in the background as usual.
>>
>> Sebastien
>>
>> ----------------------------------------------------------------------
>> --
>> *From: *"Bill Denney" <wdenney_at_humanpredictions.com>
>> *To: *"NMUsers" <nmusers_at_globomaxnm.com>
>> *Sent: *Tuesday, March 13, 2018 8:58:41 PM
>> *Subject: *[NMusers] Time-Varying Bioavailability on Zero-Order
>> Infusion
>>
>> Hi NONMEMers,
>>
>> Is there a good way to assign a time-varying bioavailabilty on a
>> zero-order rate of infusion in NONMEM? The best I’ve been able to
>> come up with is something like the below. It seems like something
>> that should be easier than what I’m doing below (I adjusted it from
>> the real example as I was typing it into the email—I could have
>> introduced a bug in the process). And importantly, -9998 is well
>> before any time in my database.
>>
>> (dosing into CMT=1 with an IV infusion)
>>
>> $MODEL
>>
>> COMP=(CENTRAL DEFDOSE DEFOBS) ; central
>>
>> COMP=(P1) ; peripheral 1
>>
>> COMP=(P2) ; peripheral 2
>>
>> $PK
>>
>> ; Normal stuff and ...
>>
>> ; Record the dosing time
>>
>> IF (NEWIND.LT.2) THEN
>>
>> TDOSE = -9999
>>
>> DOSEEND = -9998
>>
>> DOSE = -999
>>
>> DOSERATE = 0
>>
>> ENDIF
>>
>> IF ((EVID.EQ.1 .OR. EVID.EQ.4) .AND. RATE.GT.0) THEN
>>
>> TDOSE = TIME
>>
>> DOSEEND = TIME + AMT/RATE
>>
>> DOSERATE=RATE
>>
>> MTDIFF=1
>>
>> ENDIF
>>
>> MTIME(1)=TDOSE
>>
>> MTIME(2)=DOSEEND
>>
>> F1 = 0 ; Bioavailability is zero so that the $DES block has full
>> control over the rate.
>>
>> RATEADJTAU=THETA(10)
>>
>> RATEADJMAX=THETA(11)
>>
>> $DES
>>
>> ; Manually control the infusion
>>
>> RATEIN = 0
>>
>> IF (MTIME(1).LE.T .AND. T.LE.MTIME(2)) THEN
>>
>> RATEADJCALC = RATEADJMAX * EXP(-(T – MTIME(1)) * RATEADJTAU)
>>
>> RATEIN = DOSERATE - RATEADJCALC
>>
>> ENDIF
>>
>> DADT(1) = RATEIN - K10*A(1) - K12*A(1) + K21*A(2) - K13*A(1) +
>> K31*A(3)
>>
>> DADT(2) = K12*A(1) - K21*A(2)
>>
>> DADT(3) = K13*A(1) -
>> K31*A(3)
>>
>> Thanks,
>>
>> Bill
>>
>>
>

Received on Tue Mar 13 2018 - 22:41:22 EDT

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