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With respect to the query regarding dry powder versus liquid-suspension formulation, thanks for the
helpful responses; it would appear that using a lipid-based formulation for this highly lipophilic
drug (LogP = 4.5) would be a good approach.
In the short term we are looking to see if taking the drug with food reduces the variability in
systemic exposure (absorption).
The idea is to recall those healthy subjects previously dosed under fasted conditions and giving the
same dose with food.
I’m assuming that a high-fat meal would have the best chance (emulsification, improved lymphatic
uptake etc); however, we need a suitable meal that can be used for a multiple-dose study in
patients. I was considering a continental type breakfast, buttered toast and 500 mL semi-skimmed
milk?
Any suggestions on the most appropriate meal to give to the subjects would be appreciated.
Charlie Brindley
KinetAssist Limited
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Hi Charlie
Take a look at the standard fat meal that is cited in the Food-Effect Bioavailability and Fed
Bioequivalence Studies – Guidance for Industry by FDA.
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064964.htm
In brief:
A high-fat (approximately 50 percent of total caloric content of the meal) and high-calorie
(approximately 800 to 1000 calories) meal is recommended as a test meal for food-effect BA and fed
BE studies. This test meal should derive approximately 150, 250, and 500-600 calories from protein,
carbohydrate, and fat, respectively.
The following is recommended: An example test meal would be two eggs fried in butter, two strips of
bacon, two slices of toast with butter, four ounces of hash brown potatoes and eight ounces of whole
milk. Substitutions in this test meal can be made as long as the meal provides a similar amount of
calories from protein, carbohydrate, and fat and has comparable meal volume and viscosity.
Hope that helps
Manish
Manish Issar, Ph.D
Assistant Professor of Pharmacology
Western University of Health Sciences
College of Osteopathic Medicine of the Pacific
Pomona, CA 91766
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Hi Charlie
Afficionados of English breakfasts would laugh at the fat content of your continental breakfast. It
would not compare with a plateful of bacon, eggs, fried bread ( preferably in beef dripping), black
pudding and sausages full of pork, topped off with mushrooms fried in the residual oil that they are
good at absorbing. They'd have cream in their coffee and wouldn't countenance skimmed milk of any
kind. They might have died earlier than those who ate your breakfasts but they would have survived
many a bitter winter morning out in the fields in a far better humour.
I suggest you select from the above menu as much as your health and safety inspectors can be induced
to agree with.
I hope it works and when you get the result I would be intrigued to know the outcome
With my best wishes
Andy Sutton
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Hi Manish and Andy,
Thank you for your responses which are appreciated. I am aware of the recommended FDA high-fat
breakfast; however, the problem is that we are very reluctant to give this to patients every day for
two weeks.
We need a compromise that is likely to improve absorption (decrease variability) but be acceptable
to patients on a clinical trial.
We aren’t prepared at this stage to conduct a study comparing different diets.
I guess that I'm looking for some examples of a moderately fatty meal that appreciably affects
bioavailability of a lipophilic drug.
Many thanks,
Charlie
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Charlie: I would think the FDA breakfast (high fat) would be the one to standardize on as you give
the drug with food. An example of improvement in bioavailability would be clarithromycin (Biaxin
XL), which is labeled recommended to be given with food. The fats do assist dissolution by way of
emulsification and the variability is reduced.
Clearly dissolution studies should first be done to ascertain that the lipid-based formulation has
better solubility properties. That way you attempt to intercept the problem at the formulation
stage and attempt to resolve it at that stage,
Hope this helps,
Angus McLean
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Dear Charlie
In my honest opinion, if you are willing to submit this study to USFDA, you should follow the
caloric composition discussed in USFDA recommended high-fat breakfast which should derive
approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively.
Coming to your point that you are very reluctant to give the US FDA recommended high-fat breakfast
to patients every day for two weeks. In such conditions you can try other combinations of ingredient
keeping the caloric value fixed (for example try beef instead of bacon or Instead of beef and bacon
fried Chicken, Omellete, french fries (with butter) etc but the caloric contents of the composition
should be equivalent to regulatory submission otherwise they will not accept your data.
But the main issue will be the comparable viscosity. Which vegetable has a viscosity comparable to
fried bacon? How to measure viscosity of solid? or how we can compare viscocity of veg and non veg
breakfast?
We have done a couple of fed bioequivalence studies with altered ingredient or using Indian
Breakfast [VEG]. Though we had taken care of all the elements, it took a lot of correspondences to
clear the query posted by FDA authorities. FDA has a fixed mind-set that vegetarians has a different
pattern of emptying (http://www.fda.gov/downloads/Drugs/NewsEvents/UCM167292.pdf ) but with proper
justification they have agreed.
To solve the issue we even have done a viscosity test after homogenizing the meal content (veg and
non veg meal) and proved that the viscosity of homogenized meal is same for veg and non veg meal or
various different combinations.
Hope this will help
Bhupesh
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Dear Charlie
In my honest opinion, if you are willing to submit this study to USFDA, you should follow the
caloric composition discussed in USFDA recommended high-fat breakfast which should derive
approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively.
Coming to your point that you are very reluctant to give the US FDA recommended high-fat breakfast
to patients every day for two weeks. In such conditions you can try other combinations of ingredient
keeping the caloric value fixed (for example try beef instead of bacon or Instead of beef and bacon
fried Chicken, Omellete, french fries (with butter) etc but the caloric contents of the composition
should be equivalent to regulatory submission otherwise they will not accept your data.
But the main issue will be the comparable viscosity. Which vegetable has a viscosity comparable to
fried bacon? How to measure viscosity of solid? or how we can compare viscocity of veg and non veg
breakfast?
We have done a couple of fed bioequivalence studies with altered ingredient or using Indian
Breakfast [VEG]. Though we had taken care of all the elements, it took a lot of correspondences to
clear the query posted by FDA authorities. FDA has a fixed mind-set that vegetarians has a different
pattern of emptying (http://www.fda.gov/downloads/Drugs/NewsEvents/UCM167292.pdf ) but with proper
justification they have agreed.
To solve the issue we even have done a viscosity test after homogenizing the meal content (veg and
non veg meal) and proved that the viscosity of homogenized meal is same for veg and non veg meal or
various different combinations.
Hope this will help
Bhupesh
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Dear Bhupesh,
Thank you for your suggestions; however, we are not submitting this study for FDA approval. We are
simply trying to improve the bioavailability and reduce variability in systemic exposure.
We can then carry out the study in cancer patients with an appropriate breakfast. We have decided to
go with 200 mL whole milk and buttered toast.
Regards,
Charlie
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