From: "Jiang, Xuemin" xjiang1@medicine.bsd.uchicago.edu
Subject: [NMusers] sequential PKPD modeling
Date: Thu, 26 Oct 2006 09:53:07 -0500

Dear NONMEM users,

I am developing PKPD modeling of a drug which can increase blood pressure
(Drug A) simultaneously. A co-administered drug (Drug B) which can decrease
blood pressure was found to increase the CL of Drug A. I am wondering whether
the simultaneous PKPD modeling is able to confirm the finding or a sequential
PKPD modeling need to be used in this case.

Thanks

Jim Jiang
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From: "Jiang, Xuemin" xjiang1@medicine.bsd.uchicago.edu
Subject: Re: [NMusers] sequential PKPD modeling
Date: Thu, 26 Oct 2006 

Dear NONMEM users,

I would like to make my question clear. To my understanding, simultaneous analysis of PKPD
data is a better analysis especially for the sparse PK data, because the PD data can support
PK data analysis. I am wondering whether it is possible that the increasing on the CL of
drug A (in the following email) could be a consequence of PD effect of drug B rather then
a real PK effect in a simultaneous PKPD modeling.

Jim Jiang
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From: "Liping (CD) Zhang" liping.zhang3@bms.com
Subject: Re: [NMusers] sequential PKPD modeling
Date: Thu, 26 Oct 2006 15:54:50 -0400

 Hi, Jim!
"simultaneous analysis of PKPD data is a better analysis especially for the sparse PK data,
because the PD data can support PK data analysis. "
Simultaneous analysis of PKPD data is a better method because it naturally follows the maximal
likelihood theory. PD's support for PK analysis is not for granted: a misspecified PD model
could distorted PK model. For references, see Bennett and Wakefield, 2001, Biometrics, 57:803-12,
and Zhang et al, 2003, JPP: 405-16.

I assume you've had data from A alone, and data from A and B administrated, and when you model
A+B PK/PD simultaneously, you get a large Cl for A than the one from A alone? (I could only
think of this case, to support your statement "B was shown to increase the Cl of A"). If that
is the case, doing the PK modeling on A using the data A+B, and then comparing the estimated
Cl with estimated Cl from A alone, wouldn't that provide an answer?

best regards, Liping
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From: "Jiang, Xuemin" xjiang1@medicine.bsd.uchicago.edu
Subject: Re: [NMusers] sequential PKPD modeling
Date: Fri, 27 Oct 2006 09:41:12 -0500

Dear NONMEM users,

Just would like to let you know that the drug B was a significant covariate on the CL of drug
A while using simultaneous PKPD modeling but was not a significant covariate while using PK modeling
only. On the other hand, I have very sparse PK data whether it is another reason the drug B is not significant.

Many thank for the people replying the email

Jim Jiang
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