Dears
We have been working in a pk model to prove that a drug can changes its own
kinetics as a function of dose. Standards pharmacokinetics models assume a
linear relationship between dose and plasma concentrations.Till now our results
show clearly a non-linearity between dose and drug-kinetics, using dose as
covariate. But we are interested to include a dynamic covariate like CO, CI
and/or MABP as covariate using differential equation solutions .
Any suggestions, reference papers, ideas
Thanks so much
Olinto
Olinto-Jose Linares-Perdomo, BS in Electrical Engineering, M.S., Ph.D.
Biomedical Informatics Department & Pharmaceutics Department.
University of Utah-USA
Office:(801)-585-5287
Cell: 001-(801)-783-9487
Fax: (801)-581-3467
-------------------------------------
Confidentiality Note: This message is intended for use only by the individual
or entity to which it is addressed and may contain information that is
privileged, confidential, and exempt from disclosure under applicable law. If
the reader of this message is not the intended recipient or the employee or
agent responsible for delivering the message to the intended recipient, you are
hereby notified that any dissemination, distribution or copying of this
communication is strictly prohibited. If you have received this communication
in error, please contact the sender immediately and erase it
How to include a dynamic covariate
The simplest approach is using a standard, nonlinear model for clearance (e.g.,
Michaelis-Menten). However, from your apparent interest in parameters like
cardiac output (CO?) and mean arterial blood pressure (MABP?) I gather that
this drug may change blood flow to the clearance organ. As such, a
semi-physiological, organ clearance model that incorporates a pharmacodynamic
effect on blood flow seems appropriate.
Your own search for references would certainly benefit from the details that
you alone possess. However, a good overview and comprehensive list of
references that cover clearance concepts, physiological models, and some
pharmacodynamics can be found in the following commentary.
Br J Clin Pharmacol. 2005 December; 60(6): 581-583.
Physiologically based pharmacokinetic modelling: a sound mechanistic basis is
needed
L Aarons
Regards,
Jeff Wald
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Olinto Linares
Sent: Thursday, September 09, 2010 2:49 PM
To: [email protected]
Cc: [email protected]; Olinto Linares-Perdomo
Subject: [NMusers] How to include a dynamic covariate
Dears
We have been working in a pk model to prove that a drug can changes its own
kinetics as a function of dose. Standards pharmacokinetics models assume a
linear relationship between dose and plasma concentrations.Till now our results
show clearly a non-linearity between dose and drug-kinetics, using dose as
covariate. But we are interested to include a dynamic covariate like CO, CI
and/or MABP as covariate using differential equation solutions .
Any suggestions, reference papers, ideas
Thanks so much
Olinto
Olinto-Jose Linares-Perdomo, BS in Electrical Engineering, M.S., Ph.D.
Biomedical Informatics Department & Pharmaceutics Department.
University of Utah-USA
Office:(801)-585-5287
Cell: 001-(801)-783-9487
Fax: (801)-581-3467
-------------------------------------
Confidentiality Note: This message is intended for use only by the individual
or entity to which it is addressed and may contain information that is
privileged, confidential, and exempt from disclosure under applicable law. If
the reader of this message is not the intended recipient or the employee or
agent responsible for delivering the message to the intended recipient, you are
hereby notified that any dissemination, distribution or copying of this
communication is strictly prohibited. If you have received this communication
in error, please contact the sender immediately and erase it
Hello Olinto,
Here are examples of physiologically based models that included drug induced changes in blood flow and hence the drug influences its own kinetics:
1. Upton RN, Ludbrook GL. Pharmacokinetic-pharmacodynamic modelling of the cardiovascular effects of drugs - method development and application to magnesium in sheep. BMC Pharmacology 2005; 5: 5-
2. Upton RN, Ludbrook GL. A physiologically based, recirculatory model of the kinetics and dynamics of propofol in man. Anesthesiology 2005; 103: 344-52
Regards, Richard
Richard Upton
Quoted reply history
On 11/09/2010 2:55 AM, Jeff Wald wrote:
> The simplest approach is using a standard, nonlinear model for clearance
> (e.g., Michaelis-Menten). However, from your apparent interest in
> parameters like cardiac output (CO?) and mean arterial blood pressure
> (MABP?) I gather that this drug may change blood flow to the clearance
> organ. As such, a semi-physiological, organ clearance model that
> incorporates a pharmacodynamic effect on blood flow seems appropriate.
>
> Your own search for references would certainly benefit from the details
> that you alone possess. However, a good overview and comprehensive list
> of references that cover clearance concepts, physiological models, and
> some pharmacodynamics can be found in the following commentary.
>
> Br J Clin Pharmacol. 2005 December; 60(6): 581–583.
>
> Physiologically based pharmacokinetic modelling: a sound mechanistic
> basis is needed
>
> L Aarons
>
> Regards,
>
> Jeff Wald
>
> *From:* [email protected]
> [mailto:[email protected]] *On Behalf Of *Olinto Linares
> *Sent:* Thursday, September 09, 2010 2:49 PM
> *To:* [email protected]
> *Cc:* [email protected]; Olinto Linares-Perdomo
> *Subject:* [NMusers] How to include a dynamic covariate
>
> Dears
> We have been working in a pk model to prove that a drug can changes its
> own kinetics as a function of dose. Standards pharmacokinetics models
> assume a linear relationship between dose and plasma concentrations.Till
> now our results show clearly a non-linearity between dose and
> drug-kinetics, using dose as covariate. But we are interested to include
> a dynamic covariate like CO, CI and/or MABP as covariate using
> differential equation solutions .
>
> Any suggestions, reference papers, ideas
>
> Thanks so much
>
> Olinto
>
> Olinto-Jose Linares-Perdomo, BS in Electrical Engineering, M.S., Ph.D.
> Biomedical Informatics Department & Pharmaceutics Department.
> University of Utah-USA
>
> Office:(801)-585-5287
> Cell: 001-(801)-783-9487
> Fax: (801)-581-3467
> -------------------------------------
> Confidentiality Note: This message is intended for use only by the
> individual or entity to which it is addressed and may contain
> information that is privileged, confidential, and exempt from disclosure
> under applicable law. If the reader of this message is not the intended
> recipient or the employee or agent responsible for delivering the
> message to the intended recipient, you are hereby notified that any
> dissemination, distribution or copying of this communication is strictly
> prohibited. If you have received this communication in error, please
> contact the sender immediately and erase it