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Re: [NMusers] Simultaneous pk model of 2 drugs

From: Nick Holford <n.holford_at_auckland.ac.nz>
Date: Sat, 3 Sep 2016 07:31:11 +1200

Chris,

If the elimination is first-order for both drugs then its probably
computationally quicker to use ADVAN5 (or ADVAN7). This lets you specify
separate compartments to account for the input, distribution and
elimination of each drug.

The input dose is defined by the usual data items (AMT, RATE, II, ADDL,
SS) with CMT linking the input to the compartment you define with ADVAN5
(or ADVAN7).

In my opinion a user defined DVID is more flexible and a clearer way of
linking the DV with the model prediction. I use clearer to mean for a
human reading the code to understand what is intended. CMT can work
sometimes but won't work for things like effect predictions that are not
amounts in a compartment.

I am nor sure what Bill means with EVID=2 and EVID=3. EVID=2 does not
reset any compartment but it can be used to turn a compartment on or
off. It is commonly used to define a record used for prediction in
$TABLE at a time when there is no dose or observation event. EVID=3
resets all compartments. All EVIDs are subject specific.

Best wishes,

Nick


This is from the NONMEM online help. There are some minor additional features with NONMEM 7 which you can find for yourself.

  0 Observation event. The DV data item is an observation. The CMT
       data item specifies which compartment is being observed. Dose-
       related data items (AMT, RATE, II, ADDL, SS) must be zero.

  1 Dose event. The CMT data item specifies which compartment is
       being dosed. The DV data item is ignored. One or more of AMT,
       RATE, II, ADDL, SS data items must be non-zero to define the
       dose.

  2 Other-type event. The DV data item is ignored. Dose-related
       data items must be zero. Examples of other-type events are: A
       compartment is turned on or off (CMT specifies which compartment
       is to be turned on or off); a prediction is obtained at a speci-
       fied time so that it may be displayed in a table or scatterplot
       (PCMT specifies the compartment from which the prediction is
       obtained); some event occurs at a different time than any obser- |
       vation or dose event, e.g. a covariate such as weight changes, an |
       intervention such as hemodialysis is started or stopped.

  3 Reset event. The kinetic system is re-initialized. Time is
       reset to the time of the event record, the amounts in each com-
       partment are reset to zero, the on/off status of each compartment
       is reset to its initial status. The DV data item is ignored.
       Dose-related data items must be zero.

  4 Reset-and-dose event. The system is first reset, and then a dose
       is given. The DV data item is ignored.


On 03-Sep-16 07:01, William Denney wrote:
> Hi Chris,
>
> I think that the most straight-forward way to handle this is to have
> two sets of compartments and write the $DES block manually (or writing
> the algebraic equations if it's a one- or two-compartment model).
>
> It wouldn't be straight-forward to model if the subjects receive the
> drugs at the same time. If the drugs are received at separate times
> (like different periods of a study or even different studies), then
> the DVID flag idea would work, too.
>
> There are only five EVID values as far as I know, and there's not a
> subtle way to use them for two doses, I don't think:
>
> • 0= observation
> • 1= dose
> • 2= other (I usually use it to reset the compartment)
> • 3= reset the subject
> • 4= reset and dose at the same time
>
> Thanks,
>
> Bill
>
> On Sep 2, 2016, at 1:22 PM, Penland, Chris
> <Chris.Penland_at_astrazeneca.com <mailto:Chris.Penland_at_astrazeneca.com>>
> wrote:
>
>> Greetings NMusers,
>>
>> Does nonmem have the capacity, unbeknownst to me, for modeling two
>> simultaneous drugs?
>>
>> I would like some suggestions about how to define the dataset and
>> model for a subcutaneous drug and oral drug being administered on
>> different schedules. I would use DVID = 1 and 2 for the two plasma pk
>> observations. I figure this soft of thing had to be dealt with in
>> the past when trying to model dynamic DDIs (vs, just taking one of
>> the drugs as a covariate on the other’s parameters).
>>
>> One approach is to specify the compartments for each to be dosed into
>> then have those feed the central, but I’m curious to see if there is
>> something more subtle in the nonmem syntax. Is there something about
>> EVID, that I don’t know that would help (beyond EVID=1 for dosing)
>>
>> What if you had two oral drugs? Would you treat the two dosing
>> compartments as separate and possibly link them together at the
>> parameter/covariance level?
>>
>> Thanks,
>>
>> Chris
>>
>> Chris Penland, PhD
>>
>> ECD / Quantitative Clinical Pharmacology
>>
>> Waltham, MA USA
>>
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--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
office:+64(9)923-6730 mobile:NZ+64(21)46 23 53 FR+33(6)62 32 46 72
email: n.holford_at_auckland.ac.nz
http://holford.fmhs.auckland.ac.nz/

"Declarative languages are a form of dementia -- they have no memory of events"

Holford SD, Allegaert K, Anderson BJ, Kukanich B, Sousa AB, Steinman A, Pypendop, B., Mehvar, R., Giorgi, M., Holford,N.H.G. Parent-metabolite pharmacokinetic models - tests of assumptions and predictions. Journal of Pharmacology & Clinical Toxicology. 2014;2(2):1023-34.
Holford N. Clinical pharmacology = disease progression + drug action. Br J Clin Pharmacol. 2015;79(1):18-27.


Received on Fri Sep 02 2016 - 15:31:11 EDT

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