Dear groupBack to the Top
Since in Cancer patients there are lot of variables like Hepatic blood
flow, change in organ mass (if the pateint have an liver metastasis),
so my doubt is that how exactly the allometry is helpful for predicting
the pk parameters in cancer patients using the normal variables like
animal body weight, brain weight or clearnace from preclinical study.
As the clearnace, volume of distributionof compound in normal animals
is different from cancer patients.
Is PK data carried out in tumor bearing animals is useful for allometry
predicting.
Thanks
Regards
Venkatesh .P
Venkatesh.P
Senior Pharmacologist,
Dept of Drug Metabolism and Pharmacokinetics,
Discovery Research, Dr.Reddy's Labs.
Hyderabad, India-500050.
Phone no:91-9849692908
PharmPK - Discussions about PharmacokineticsBack to the Top
Pharmacodynamics and related topics
Venkatesh P. wrote,
"Dear group, since in Cancer patients there are lot of variables like
Hepatic blood flow, change in organ mass (if the pateint have an liver metastasis), so my doubt is that how exactly the allometry is helpful for predicting the pk parameters in cancer patients using the normal variables like
animal body weight, brain weight or clearnace from preclinical study."
Dear Venkatesh P.
Maybe you should have a look these papers:
YS Lin et al., Preclinical PK, Interspecies Scaling and Tissue
Distribution of a Humanized Monoclonal Antibody against Vascular Endothelial Growth Factor. The Journal of Pharmacology and Experimental Therapeutics. 1999;
288:371-378
I Mahmood, Interspecies scaling: predicting clearance of anticancer
drugs in humans. A comparative study of three diferent approaches using body
weight or body surface area. Eur. J Drug Metab & PKs. 1996; 21: 275-278.
see also RL Dedrick et al., Cancer Chemother. Rep., Part 1, 54: 95-101,
1970.
Based on allometry, YS Lin et al. (1999) presented a comparison of the
predicted and observed PK of rhuMAb VEGF in humans, reporting a
clearance value in humans comparable to the value noted in cancer patients.
As a matter of fact, it is a topic which we (me and co-workers at Pk
Lab, University of Havana) have been dealing with during last time.
Actually, we developed interspecies scaling of MAb ior R3 anti-EGFreceptor (with
supported efficacy against breast, neck-head and pulmonary cancer)
using 4 mammal species following allometry and our results showed that the drug
clearance was more than four-fold lower than the observed value in
cancer patients (0.22 ml/h/kg versus 0.98 ml/h/kg). We assumed this result was
reasonable considering disease state (i.e., cancer). Currently, these
results are due for press in Biopharmaceutics and Drug Disposition.
IMHO, I guess we probably need to use others covariates (perhaps energy [O2]
consumption, metabolic rates, MDR gene expression, etc) in order to
scale-up PK of anticancer drugs taking into consideration the several
complexities of this pathology. As far as I know, allometric pardigm is not much
interested in explaining PK differences between patients (disease state) and
healthy subjects, rather it is a general biological regularity for scaling
responses by using body weight as covariate. That is, it is telling us the
expected mean value for a typical mammal of the given size, and the real world
will always deviate more or less from this idealized norm, especially if we
are talking about disease.
Notice that our endpoint was to elucidate whether using the allometry is
possible to predict the ior R3 kinetic behaviour in human, and
particularly in cancer patients, following a comparison between predicted and
observed values in a similar manner as reported by Lin et al., 1999. If so, we
could use the allometric tools for selecting the first-time in human ior R3
dose.
A discussion about the plausibility of using this algorithm to reveal
similarities and differences of the ior R3 disposition pattern in cancer
patient with respect to healthy humans, a questionable but interesting
point, was aimed in this study. In this context, the comparison between
predicted and observed values was used in order to corroborate or reject
this hypothesis.
Hope this help you,
Regards,
Jorge Duconge
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