Dear all,Back to the Top
I am greatful if any one tell about the PK-PD correlation for the
anti-cancer drugs. If any publications related to this subject will be
mind blowing.
Also please share any information on basic biomarkers other than
CT-scaning for the anti-cancer treatment out come.
Regards and thanks
Venkatesh.P
Senior Pharmacologist,
Dept of Drug Metabolism and Pharmacokinetics,
Discovery Research, Dr.Reddy's Labs.
Hyderabad, India-500050.
Phone no:91-9849692908
[The book, Derendork, H. and Hochhaus, G. 1995 Handbook of
Pharmacokinetic/Pharmacodynamic Correlation, CRC Press has a chapter on
this topic - db]
The paper written by Simeoni et al., Cancer Research 64:1094-1101, 2004Back to the Top
may
be helpful. Another, Karlsson et al., Clin. PHARMACOL Ther. 1998; 63:
11-25.
However, it seems to me that many authors do have difficulty in linking
tumor growth inhibition to blood concentrations of cancer drugs.
Characterization of these dose-concentration-effect relationships
remained
in most cases limited to drugs with a straight correlation between
observed
effect and measured concentration (such as cardiovascular drugs), and
failed
if the intensity of effect lagged behind the concentrations and time
course
(such as cancer drugs)
Lee Jia, PhD.
Project Officer
Developmental Therapeutics Program
Division of Cancer Treatment and Diagnosis
NCI/NIH
Jia, Lee (NIH/NCI)" wrote:Back to the Top
"However, it seems to me that many authors do have difficulty in linking
tumor growth inhibition to blood concentrations of cancer drugs.
Characterization of these dose-concentration-effect relationships
remained in most cases limited to drugs with a straight correlation
between
observed effect and measured concentration (such as cardiovascular
drugs), and
failed if the intensity of effect lagged behind the concentrations and
time
course(such as cancer drugs)"
The comments by Lee Jia about the difficulty of relating blood
concentrations of cancer drugs to tumour growth inhibition reflect a
somewhat limited view of PKPD modelling i.e. "straight correlation
between observed effect and measured concentration". It has been noted
for a long time (e.g. Holford & Sheiner 1981) that there is commonly a
delay between the time course of blood concentration and observed
effect. Models involving either a distributional delay ("the effect
compartment model") or a physiological turnover delay (e.g Simeoni et
al. 2004 [cited by Lee Jia]) are capable of describing delayed effects
and have been widely used in many areas other than cardiovascular drugs
to explain slow onset of observed drug response.
The rather disappointing lack of clear cut examples of the ability of
PKPD models to predict the response to cancer chemotherapy in humans
may also be based on the use of the pharmacologically naive use of area
under the concentration curve (AUC) as the exposure variable. AUC
approaches discard information about the time course of concentration
and thus cannot explain the well known phenomenon of schedule
dependence.
The failure of PKPD models "if the intensity of effect lagged behind
the concentrations and time course(such as cancer drugs)" is unlikely
to be a property specific to anti-cancer drugs but is perhaps better
explained by the use of inappropriate models and inadequate
experimental designs for observing the time course of tumour response.
Holford NHG, Sheiner LB. Understanding the dose-effect relationship:
clinical application of pharmacokinetic-pharmacodynamic models.
Clinical Pharmacokinetics 1981;6(6):429-53
Simeoni M, Magni P, Cammia C, De Nicolao G, Croci V, Pesenti E, et al.
Predictive Pharmacokinetic-Pharmacodynamic Modeling of Tumor Growth
Kinetics in Xenograft Models after Administration of Anticancer Agents.
Cancer Res 2004;64(3):1094-1101.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
Hi!Back to the Top
Alan Forrest and Merrill Egorin have a whole series of publications on
this in the cancer literature.
George Drusano
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