Dear GroupBack to the Top
Can Creatinine Clearance be used as an PD parameter for
PK-PDcorrelation of an anti cancer drugs in clinical patients.
Regards
Venkatesh.P
Senior Pharmacologist,
Dept of Drug Metabolism and Pharmacokinetics,
Discovery Research, Dr.Reddy's Labs.
Hyderabad, India-500050.
"Venkatesh. P" wrote:Back to the Top
"Can Creatinine Clearance be used as an PD parameter for
PK-PD correlation of an anti cancer drugs in clinical patients."
Creatinine clearance (CLcr) is usually used a covariate to predict
renal function. In population modelling terms it can be considered a
form of independent variable ("X"). It is not usually a model parameter
(i.e. a constant) such as clearance in a PK model.
It is certainly reasonable to use CLcr as a covariate to explain some
between subject variability in the parameters of a PKPD model. The
parameters could be PK e.g. clearance and/or PD e.g. Emax.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
Venkatesh,Back to the Top
I assume you are using this as a correlation of toxicity in
patients in certain chemotherapy regimens?
Regards,
J. Christopher Spell, Ph.D.
Medical Science Liaison - Hematology/Oncology
Global Medical Affairs
Wyeth Pharmaceuticals
Phone: (203) 288-4828
E-mail: spellj2.-at-.wyeth.com
To add to Nicks comment:Back to the Top
"It is certainly reasonable to use CLcr as a covariate to explain some
between subject variability in the parameters of a PKPD model. The
parameters could be PK e.g. clearance and/or PD e.g. Emax."
It could also be a surrogate response for a PD model where the outcome
of interest was nephrotoxicity.
Steve
Stephen Duffull
School of Pharmacy
University of Queensland
Brisbane 4072
Australia
Tel +61 7 3365 8808
Fax +61 7 3365 1688
University Provider Number: 00025B
Email: sduffull.aaa.pharmacy.uq.edu.au
www: http://www.uq.edu.au/pharmacy/sduffull/duffull.htm
PFIM: http://www.uq.edu.au/pharmacy/sduffull/pfim.htm
MCMC PK example: http://www.uq.edu.au/pharmacy/sduffull/MCMC_eg.htm
Dear Venkatesh,Back to the Top
1. Creatinine clearance (CLcr) is generally used as an explanatory
variable or covariate to describe some variability in the systemic clearance of
drugs (CL=function(CLcr). That is, CLcr is a variable (usually an independent
variable) and not a parameter (unlike CL or Volume, ka etc.,) that is
estimated using concentration data. This was what essentially Nick was
implying.
2. Your question, if I can 'guess' correctly, is about using CLcr as a
pharmacodynamic marker. The answer is Yes. If you would like to test
whether the drug affects the renal function, as a desired or undesired effect,
you can develop a relationship between concentration of the drug and CLcr
over time. Some oncologic drugs are known to affect renal function. CLcr only
reflects the GFR and not necessarily other renal functions. It might be
useful to discuss with an appropriate person regarding the potential
mechanism of action. If this is not what you meant, please ignore my
comment.
Regards,
Joga Gobburu
I can imagine cases where creatinine clearance may provide some insightBack to the Top
into drug action (renal toxicity, changes in cardiac output, renal
perfusion, etc...). However, as an endogenous substrate there are two
sides to the creatinine equation...production and clearance...and I can
imagine as many or more factors to change production, particularly in
cancer and cancer chemotherapy, than I can think of to change its
clearance.
Even if creatinine clearance is to be used just as an exploratory PD
marker, I would absolutely recommend against using the quick and dirty
approaches to its estimation like the Cockroft-Gault equation. To
really
measure renal function as a PD endpoint, I'd look for something more
definitive and would likely want to look at multiple markers of renal
function (GFR, perfusion, active processes, etc) depending on the
supposed
mechanism of drug action.
Jeff
Jeff Wald, PhD
jeffrey.a.wald.aaa.gsk.com
Clinical Pharmacokinetics/Modeling and Simulation
Neurology and GI
RTP, NC
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