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Group: What would be the best approach to select the dose for first
clinicals (beyond the classical AFDO guidelines) if the drug shows
higher interspecies variability in metabolic pathways (e.g., scaling
not possible).
Look forward to your input. Thanks
N. N. S
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Group: What would be the best approach to select the dose for first
clinical (beyond the classical AFDO guidelines) if the drug shows
higher interspecies variability in metabolic pathways (e.g., scaling
not possible).
Look forward to your input. Thanks
N. N. S
I will start first dosing comfortably doing good pre clinical work with the
drug and identify an animal model that best represent or come very close
to human, then start a conservative dose escalation study with well
defined pharmacodynamic variable to watch for and establish a
relationship with Cmax - PD response or clinical compliance. Once this
relationship is established continue classical clinical studies with heavy
emphasis on Therapeuitc Drug monitoring. Best I could think is the
following order.
1) In vitro liver microsomal work to identify possible metabolites in various
species including Human. Some times we have to go beyond classical
three species approach ( In one case we investigated beyond 6 species
to test the animal model and found Baboon a good animal model close to
Human)
2) Try to identify primary isoform responsible the metabolism of the drug.
3) comparative PK in three animal models that are close to human from
the # 1 study.
4) These three studies give good idea in designing first time in Man study.
My impression is for this type of problematic(assuming all the troubles
listed are true) -- Good emphasis in Phase I studies and therapeutic drug
monitoring will save lot of confusion during the large clinical studies.
Hope this helps to initiate good discussion,
Regards,
Prasad N.V. Tata, Ph.D.
Otsuka America Pharmaceutical Inc.
PS: Opinions expressed are my professional opinions not my employers
Also see: http://www.cpb.uokhsc.edu/pkin/pkin.html
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In such cases the first dose may not be as important as the rate of dose
escalation. The first dose is where one starts a journey. Without the
correct road map it may be impossible to find the destination.
The first dose of a new drug in humans should always be conservative and
based on a good preclinical work-up. However, one also would want to
discover the maximally tolerated dose (MTD) in a timely fashion.
Although you do not know what the plasma concentrations will be, you may
have useful information regarding the slope of concentration response
relationships (therapeutic and toxic) from animal pharmacology studies.
Once you have discovered where you lie on the concentration axis of that
curve in humans (e.g., after the first one or two dose levels) you will
be able to rationally expedite the search for MTD.
In addition, I would explore the in vitro metabolism in human liver
preparations. That should at least give you 'order-of-magnitude'
estimates.
Regards,
Jeffrey Wald, Ph.D.
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