Back to the Top
Is there any consensus on a reliable animal model to predict the effect of food (fed) in man on absorption?
dave
Back to the Top
Hi Dave, assuming that one needs food effect repines data on a Phase III trial batch and/or a final to-be-marketed product and assuming we are dealing with commonly used solid dosage forms (tablets or capsules, one can not use small animals (rats, mice, etc). Studies in monkeys would be expensive and cumbersome. So, this leaves dogs as the most practical species for conducting food effect studies. I have used dogs in the past for food effect studies and the results were very useful. Here again, use of dogs is only for formulation screening as to what would be the best formulation to proceed for clinical study. It is the human study that counts for regulatory submissions.
Hope this helps.
Aziz Karim, PhD, FCP, ABCP
AzK Consulting, Inc
azia_karim.-a-.yahoo.com
Back to the Top
The following message was posted to: PharmPK
Dave,
You asked:
Is there any consensus on a reliable animal model to predict the effect of
food (fed) in man on absorption?
In our experience, the best animal is man, and even that is not always
predictive. Ethnic and dietary differences can result in significant
differences in fed state absorption and PK. In our consulting work, we've
seen examples of very different fed state behavior between groups when
fasted state was similar.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
Back to the Top
Dear David,
Looking at the physicochemical properties, permeability and solubility (BCS class), of your compound should already give a good idea about possible food effects. And it is quite easily tested in early clinical studies (say First time in Human).
C. Wu and L. Benet. Predicting drug disposition via application of bcs: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharmaceutical research, 22(1):11-23, 2005
Bart
Bart Laurijssens
BEL Pharm Consulting
Moulin d'Ozil
07140 Chambonas
France
Back to the Top
The following message was posted to: PharmPK
Hello Aziz, my old friend, you are right to share with us your experience.
May I add that you can now also simulate quite effectively the effect of
food in the new absorption simulator (ADAM) of Simcyp. That can help you
limit you clinical experiments to the most relevant cases, or argue with the
authorities that food is unlikely to have an effect. Remember that the FDA
can verify all your claims and simulations since they run Simcyp themselves.
Regards,
Joachim
Joachim Grevel, PhD
Scientific Director
BAST Inc Limited
BioCity Nottingham
Pennyfoot Street
Nottingham, NG1 1GF
Back to the Top
Just a note regarding Walt Woltosz comment. Difference in fed state in different studies are most likely related to the fed content of the meal (high fat meal has profound physiological effect) and time of drug dosing relative to food intake 9longer this time period. less the food effect response). It is for this reason why FDA guidance which includes both the meal content (high fat meal) and time of dosing (immediately after completing the meal) should be strictly followed in conducting the food effect studies Time taken to complete ingestion of meal also affects food effect response. It should not exceed 30 minutes.
In food effect studies we are trying to evaluate how the dosage form will behave under optimal conditions to affect drug absorption. In this regard it is really a quality control check on the dosage form. I make this statement because it is offend asked that no one takes high fat breakfast on daily basis..
Regards,
Aziz Karim
Back to the Top
The following message was posted to: PharmPK
Walt,
Was just wondering if the differences in absorption and pk you have seen
in fed/fasted studies with diverse ethnic/dietary groups has the
potential to adversely skew BE food studies conducted for ANDA's.
Based on your comments it would seem there should to be some concern. I
assume these concerns have been answered since it appears more and more
studies are being conducted on foreign soil. Is there an official
EMEA/FDA position?
Art Straughn, Pharm.D.
Professor Emeritus Pharmaceutical Sciences
astraughn.-at-.uthsc.edu
Back to the Top
The following message was posted to: PharmPK
Good point, Bart - it is becoming a pretty routine matter to take a look at this in the FTIH study(s). We routinely do it in pilot fashion, not powered as a formal food effect study would be, in 6-8 subjects at a dose of perhaps 1\4 - 1\3 of the known or projected MTD. These findings have been particularly useful to companies that are trying to choose from a series of related leads, they can use these data with the animal data and simulation software like SIMCYP and get a pretty good idea of what's going on, well in advance of the fully-powered studies done to meet the guidance documents.
--dean
Dean W. Knuth President & CEO Jasper Clinical Research & Development, Inc. 526 Jasper Street Kalamazoo MI 49007
Back to the Top
The following message was posted to: PharmPK
Bart:
BCS class and the BDCCS classification system proposed by Benet are not equivalent. The BCS classification should NOT be substituted for BDCCS class.
I analyzed the reported BCS classification for all drugs approved by the FDA from 1999 through 2008. There was a inconsistency among the drugs as to the type of data used to make this classification....46% of drugs were classified based on some type of in vitro data as opposed to a clinical mass balance study. Two thirds of drugs categorized as Class IV based on in vitro data did not behave consistent with the BDCCS Class IV.
This data was presented last year at the ASCPT and I can send you the poster if you like.
Carol Collins
Back to the Top
Hello Joachim, how wonderful to hear from you. I remember all the stimulating discussions we had in the past at various international meetings. I agree with you entirely that with availability of modern tools in drug development one is able to get extensive information on a drug candidate prior to dosing in humans. However, I do think that we should incorporate the past experience and knowledge into the newer technologies (eg, SynCyp, etc) so that most reliable information can be gathered using all the available data. For example I had proposed that Biopharmaceutical Classification System (BCS) can be a very powerful tool to predict the direction of food effect response. This approach gives you reliable information most of the time but like any other approaches there are always some exceptions. For example:
1) High-Solubility-High-Permeability Drugs (BCS Class I). These drugs are absorbed throughout the gastrointestinal (GI) tract and they have little to no significant food induced changes on the systemic availability (AUC) after oral dosing. There might be some delay in Tmax but this is not critical for chronically administered drugs.
2) Low-Solubility-High-Permeability Drugs (BCS Class II). For these drugs, rate of dissolution becomes the rate limiting step in oral absorption and these drugs can have pronounced food-induced increases in the systemic availability. These drugs are most critical in so far as food effect response is concerned. Sooner we find out the food effect response in man for BCS Class II drugs, the better it will be in the long run. I have come across as much as three to four fold increase in food-induced systemic availability of Class II drugs and here there is always a danger of producing toxic plasma concentrations.
3) High-Solubility-High-Permeability Drugs (BCS Class III). These drugs tend to have opposite food effect response to Class II drugs. Food, in fact, may reduce systemic availability. Again it is important to know early in drug development if this phenomenon is present so that proper dosing recommendations are instituted during further clinical drug development. I agree with Dean Knuth that the food effect response of an experimental drug should be evaluated as early as possible in drug development.
4) Low-Solubility-Low-Permeability Drugs (BCS Class IV). These drugs are intended for local treatment in GI tract and they do not produce systemic levels when given with or without food.
There are of course exceptions to the above rules, especially for drugs that undergo extensive first-pass metabolism. Here the portal blood flow overrides the permeability factor and the above rules may not be a good predictor of food effect response.
I am sorry for such a long message but the point I wanted to make is past experience is invaluable and should not be ignored when using the modern tools and software.
With my very best wishes and regards,
Aziz
Back to the Top
Dear Carol,
Understood, and yes, please send me the poster. Thanks.
However, the point I was trying to make was that the physicochemical properties of the compound will give you an idea about the likelihood and nature of food effects (and other information, such as PK (especially F) in 1 or 2 preclinical species will help as well).
I am not convinced that special food effect studies in animals are needed or even justified.
Bart
Bart Laurijssens
BEL Pharm Consulting
Moulin d'Ozil
07140 Chambonas
France
Back to the Top
The following message was posted to: PharmPK
Bart:
I completely agree with you that we need to look closer at the physical-chemical properties of compounds and that we should use this data to predict their clinical pharmacokinetic properties. But I would like to see more consensus on what constituents acceptible data both in terms of in vitro data (what cell system, what cutoffs) and even clinical studies such as mass balance.
I will send the poster separately.
Carol
|
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Animal Model for Food Effects in Man" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)