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RE: [NMusers] Simultaneous pk model of 2 drugs

From: Chang, Cheng <Cheng.Chang_at_pfizer.com>
Date: Wed, 7 Sep 2016 14:33:04 +0000

I second Leonid's approach, which is straightforward and scalable to more than two drugs. Even when the two drugs don't interact at the PK level, this approach could still be beneficial in quantifying the common physiological processes that are perturbed by both drugs (if that's the case). I have an example of estimating one set of system parameters based on the simultaneous modeling of three different compounds from separate studies. The work is currently under journal review and I'll be happy to share the code if interested.

Thanks,

Cheng Chang, Ph.D.
Systems Modeling & Simulation
Department of Pharmacokinetics, Dynamics and Metabolism
Pfizer Inc.
Groton, CT
(860) 686-9240

-----Original Message-----
From: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com] On Behalf Of Leonid Gibiansky
Sent: Friday, September 2, 2016 4:01 PM
To: William Denney; Penland, Chris
Cc: nmusers_at_globomaxnm.com
Subject: Re: [NMusers] Simultaneous pk model of 2 drugs

I think there is no difference between simultaneous administration or not as the dose is directed to the appropriate compartment using CMT variable. In any case two dosing records (one for each drug) are needed, and the relative times of these records are not important. So it is exactly like two models (one for each drug) written in one control stream (with different compartments used for each drug). CMT is used to direct the dose. DVID or CMT can be used to identify observations for each drug. Interactions can be studied using correlations of random effects, or using joint parameters, or directly specifying how concentration of one drug influences the parameters of the other drug.
Regards,
Leonid

On 9/2/2016 3:01 PM, 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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Received on Wed Sep 07 2016 - 10:33:04 EDT

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