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Dear friends,
I am working on PK study of a drug. The drug has three metabolites in human. The problem is that how to choose a good animal model to do the PK study.
First experiment, I tried to study the in vitro kinetic experiment of human, rat, rabbit, and monkey hepatic microsomes. I found the metabolic profiles are difference from species. Only monkey has similar metabolic profile with human (the metabolites ratio is similar with human;
intrinsic clearance CLin is similar with human; but apparent Km is 2 times lower than human )
Second experiment, I used the CYP antibodies and CYP chemical inhibitors, the results show that the same inhibition happened in human and monkey's hepatic microsomes.
From these two experiments, I just can get conclusions:
1. Human and monkey has same metabolic profile.
2. The inhibitor, which can inhibit human's CYP, also can inhibit monkey's CYP.
But only from results of these two experiments I cannot prove that there is the same CYP involved in the human and monkey.
Does somebody can give advices how to prove that the monkey could be qualified animal model of PK study?
Or if you have some references of how to choose animal model for PK study, could you please share to me?
Thanks,
Guo
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It depends on the purpose of your doing PK study.
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The following message was posted to: PharmPK
Guo,
I am wondering why you need to do a study in animals when you could
get more useful information from a microdosing study in man (assuming
you have suitable tox data).
Moreover, I think it is unethical to sacrifice primates for such a
small scientific advance.
Andrew
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Hi Guo,
It looks like in this case monkey would be a good model but picking an animal model would depend on what you are looking in PK studies. In this situation, you can pick any animal model as long as you are
1) not looking for unique metabolite in PK studies that is present in humans
2) your compound has not high clearance in human microsomes in contrast to other species such as rat or dog microsomes picked for PK studies.
3) not using PK study for PKPD to predict human dose.
Hope this is helpful.
Thanks,
Raj
Rajinder Bhardwaj
DMPK
Lundbeck Research USA
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Yeah,
animal model just a tool to test your idea, so your purpose is the kernel
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Hi,
A PD/TOX animal is conventionally employed for PK screen.
nHistoric know-hows: (analogue based research and/or fast follower approach).
Feedback from first-in-man studies aid in restrategising and/or enhancing early PK screening using a single rodent species. There is no hard rule in selecting an animal for a PK study. PK is always used for interpretation of observed PD/TOX effects.
Regards
L.V.Chakradhar
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Dear Guo
First tell us whether you are working on NCE or Generic drug ?
Generally PK studies are done to support the efficacy studies. So ideally you have to do PK study in the same species in which you are doing efficacy studies. As you mentioned, your drug forms three metabolites. Are they pharmacologically active ? If yes then you should quantify those and should take in to account the selection of species for pharmacokinetics study of particular metabolite. For selecting the species for toxicity studies, people take in to account the metabolic pattern of the drug. Animal species showing metabolic pattern similar to human would be selected for toxicity studies. Here your aim is drug and its metabolites should be in higher concentration so that you can assured its safety in human.
For pharmacokinetics study, unless and untill species selected for efficacy studies wont form the pharmacologically active metabolite, then only you can select species which forms it. Otherwise species selected for efficacy studies would be ideal to carry out PK study.
I think this will help you.
regards
Dr. Amol A Raje
Preclinical division
Vimta Labs Limited
5, S. P. Biotech Park, Genome Valley
Turkapally, Shameerpet
Hyderabad -500 078
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