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Dr Andrew Leary ★ Ireland, 2010-08-24 14:13 (5768 d 07:54 ago) Posting: # 5823 Views: 7,560 |
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Hello Helmut and co. I trust that heatwave and floods are over and that you're having good weather for the last part of summer. The sun is shining here in Ireland!  Does anyone have a view on the timing of the high fat breakfast? In the past we've used (a) breakfast to start 30min before dosing (to be completed prior to dosing), and (b) breakfast to start immediately after dosing. I guess it is also possible to dose subjects when they're halfway through breakfast. Is there any evidence (or guidance) to support one approach over another? Is one approach likely to increase variability compared to another? All opinions / comments gratefully received!  Kind regards |
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d_labes ★★★ Berlin, Germany, 2010-08-24 15:00 (5768 d 07:07 ago) @ Dr Andrew Leary Posting: # 5824 Views: 6,800 |
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Hello Andrew! ❝ The sun is shining here in Ireland! Happy Ireland  . In Kiel, where I'm going today it is ever raining.❝ Does anyone have a view on the timing of the high fat breakfast? ... ❝ Is there any evidence (or guidance) to support one approach over another? See the new EMA guidance, 4.1.4 Study conduct, page 8: "In case the study is to be performed during fed conditions, the timing of administration of the drug product in relation to food intake is recommended to be according to the SmPC of the originator product. If no specific recommendation is given in the originator SmPC, it is recommended that subjects should start the meal 30 minutes prior to administration of the drug product and eat this meal within 30 minutes." Seems this is not restricted to only high fat. See further FDA Guidance "Food-Effect Bioavailability and Fed Bioequivalence Studies", page 6: "Fed Treatments: Following an overnight fast of at least 10 hours, subjects should start the recommended meal 30 minutes prior to administration of the drug product. Study subjects should eat this meal in 30 minutes or less; however, the drug product should be administered 30 minutes after start of the meal. The drug product should be administered with 240 mL (8 fluid ounces) of water. No food should be allowed for at least 4 hours post-dose." May be other guidances have also some timing suggestions. Too lazy to read it for you  .❝ ... Is one approach likely to increase variability compared to another? Don't know. — Regards, Detlew |
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ElMaestro ★★★ Denmark, 2010-08-24 17:09 (5768 d 04:58 ago) @ d_labes Posting: # 5825 Views: 6,830 |
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Ahoy, ❝ "In case the study is to be performed during fed conditions, the timing ❝ of administration of the drug product in relation to food intake is ❝ recommended to be according to the SmPC of the originator product. If no ❝ specific recommendation is given in the originator SmPC, it is recommended ❝ that subjects should start the meal 30 minutes prior to administration of ❝ the drug product and eat this meal within 30 minutes." Assuming it takes at least 5 minutes to get from the breakfast area and into the clinic or dosing room, I propose the following mandatory paragraph in all new protocols in section 4.7.1.43.8.18:: "Persons not capable of inhaling 5 donuts, a bagel with cream cheese, 2 bowls of Honey Crust Loop Bomb Speed Wafers with whole milk, a half water melon, and 16 oz. of orange juice, in 25 minutes while reading the Bangalore Gazette or Toronto Times are excluded." — Pass or fail! ElMaestro |
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Dr Andrew Leary ★ Ireland, 2010-08-24 18:22 (5768 d 03:46 ago) @ ElMaestro Posting: # 5827 Views: 6,720 |
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You are The Maestro. We're not worthy!  |
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Helmut ★★★   Vienna, Austria, 2010-08-24 18:34 (5768 d 03:33 ago) @ ElMaestro Posting: # 5828 Views: 6,720 |
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Ahoy, ❝ "Persons not capable of [...] reading the Bangalore Gazette or Toronto Times ❝ are excluded." Come on, I'm sure you don't force illiterates amongst your crew to walk the plank.  — Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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Dr Andrew Leary ★ Ireland, 2010-08-24 18:20 (5768 d 03:47 ago) @ d_labes Posting: # 5826 Views: 6,702 |
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OK, now I'm embarassed.  I've read the guideline at least 3 times in the last 8 months but had obviously missed / forgotten this. This is the problem with ever-lengthening guidelines! Many many thanks. I hope the rain stops soon. |
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Pavidus ● 2010-08-25 16:11 (5767 d 05:56 ago) @ Dr Andrew Leary Posting: # 5829 Views: 6,635 |
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Dear all, allow me to ask for clarification on this issue using the following example: exemestane SmPC says: "tablet...preferably after a meal." (i.e. there is no specification if after "high-fat meal", or no). So I would perform the BE study under fed conditions. Now, according to the valid GL (page 10): In studies performed under fed conditions, the composition of the meal is recommended to be according to the SmPC of the originator product. If no specific recommendation is given in the originator SmPC, the meal should be a high-fat ergo I would do the BE after high-fat breakfast. Is this correct? Thank you in advance. KR, Pavidus |
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Dr Andrew Leary ★ Ireland, 2010-08-25 16:52 (5767 d 05:15 ago) @ Pavidus Posting: # 5831 Views: 6,670 |
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Greetings, Pavidus! ❝ I would do the BE after high-fat breakfast. ❝ Is this correct? In my view, you are correct. Do we need any more evidence that (aspects of) the new GL are insane? There are very few SmPCs that specify the particular meal to be taken before or with or after the drug in question. So now we have no choice but to go for a meal composition which pushes variability to the maximum. Which Europeans (apart from some of my fellow Irishmen) eat a breakfast of 800 to 1000 calories with 50% fat? Kind regards Andrew |
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ElMaestro ★★★ Denmark, 2010-08-25 17:14 (5767 d 04:54 ago) @ Dr Andrew Leary Posting: # 5832 Views: 6,631 |
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Hi Pavidus and Andrew, I concur. In fact, I'd love to see the guideline logic applied to Regenon. European SPCs say that it should be taken a half or whole hour after a meal, of course without really specifying what the meal is like. So, we'd basically have to go for a fed study w/ high-fat meals for a tablet intended (4.1) for weight loss in conjunction with diet.  — Pass or fail! ElMaestro |
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Ohlbe ★★★ France, 2010-08-25 18:07 (5767 d 04:00 ago) @ Dr Andrew Leary Posting: # 5835 Views: 6,653 |
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Dear Andrew, ❝ Which Europeans (apart from some of my fellow Irishmen) eat a ❝ breakfast of 800 to 1000 calories with 50% fat? I had a very high opinion of the English breakfast, until I went to Ireland... I'm still salivating when thinking of the breakfast menu at my hotel... Why are my fellow Frenchmen, so proud of their cuisine (and with every reason to be), satisfied with just some bread and butter and jam, and a cup of coffee ? Regards Ohlbe — Regards Ohlbe |
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Dr Andrew Leary ★ Ireland, 2010-08-25 18:15 (5767 d 03:53 ago) @ Ohlbe Posting: # 5836 Views: 6,626 |
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❝ Why are my fellow Frenchmen, so proud of their cuisine (and with every ❝ reason to be), satisfied with just some bread and butter and jam, and a ❝ cup of coffee ? Ah, but Ohlbe, the French have proper coffee and proper bread... |
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Dr_Dan ★★ Germany, 2010-08-25 17:33 (5767 d 04:35 ago) @ Pavidus Posting: # 5833 Views: 7,084 |
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Dear all Exemestane absorption is significantly affected by concomitant ingestion of food. Concomitant intake with food increases the bioavailability by 40%. Section 3.2.2 of the old BE Guideline states that if the SPC of the reference product contains specific recommendations in relation to food intake related to food interaction the study should be designed accordingly. According to the Questions & Answers on the Bioavailability and Bioequivalence Guideline (EMEA/CHMP/EWP/40326/2006) the recommendations concerning food intake in the SPC are not sufficient for regulatory decisions on the adequacy of bioequivalence studies. It is pointed out in this document that if the recommendation of food intake in the SPC is based on pharmacokinetic properties such as higher bioavailability, then a bioequivalence study under fed conditions is generally required. Unfortunately it is a weakness of the originator's SPC to state that exemestane tablets are to be taken "once daily preferably after a meal" keeping in mind the decreased bioavailability when administered in the fasted state. Ingestion of the drug under fasting conditions may result in plasma levels below the minimum effective concentrations, which is an unfortunate situation for patients and could be discussed as a potential serious risk to public health. Since all Phase III studies were performed in the fed state the efficacy of exemestane 25 mg given in the fasted state is not proven. The FDA approved PIL therefore clearly states "Take your dose of AROMASIN once a day, every day, after a meal." I know that with the next revision of the European SPCs and PILs the text will be adapted in that way that Aromasin (or any other exemestane formulation) has to be taken with a meal. Several regulatory authorities accepted the argumentation given above. If you have any question please contact me. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Dr_Dan ★★ Germany, 2010-08-25 17:49 (5767 d 04:19 ago) @ Dr_Dan Posting: # 5834 Views: 6,661 |
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Hi all another interesting aspect: "In general, a bioequivalence study should be conducted under fasting conditions as this is considered to be the most sensitive condition to detect a potential difference between formulations." (CPMP/QWP/EWP/1401/98 Rev. 1). But what to do if the drug can not be administered in the fasted state due to gastro-intestinal complications? Also in these cases the SmPC does certainly not contain any information about the composition of a meal to be taken. What should we do if the rate of absorption is reduced after giving a high-fat meal compared to fasting conditions. The Q&A document points out that: "The composition of the meal should be described and taken into account, since a light meal might sometimes be preferable to mimic clinical conditions, especially when the fed state is expected to be less sensitive to differences in pharmacokinetics." Accordingly a bioquivalence study under fed conditions with a standardized non high-fat meal should be indicated. From a scientific point of view a bioequivalence study with an administration of a standardized non high-fat meal is more sensitive to detect differences in formulations than a study with the administration of a high-fat and high-calorie meal, but this is not the point of view of the regulatory authorities, as shown on the EGA meeting held in London on June 1st. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Helmut ★★★ Vienna, Austria, 2010-08-25 18:22 (5767 d 03:45 ago) @ Dr_Dan Posting: # 5837 Views: 6,745 |
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Dear Dan! ❝ The Q&A document points out that... True, but the Q&A document is history. The BE-GL states "This guideline [...] replace the [...] related questions in the Q&A document (CHMP/EWP/40326/06)." ❝ [...] this is not the point of view of the regulatory authorities, as shown ❝ on the EGA meeting held in London on June 1st. Exactly. High-fat, high-calory, full stop.  Good luck to all volunteers in a steady state study.— Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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Pavidus ● 2010-08-26 12:02 (5766 d 10:05 ago) @ Helmut Posting: # 5838 Views: 6,580 |
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Dear all, thank you for the discussion. According to the valid GL a BE study with "normocaloric" breakfast would be (extremely) rare. Have a nice day! KR, Pavidus |
Ing. Helmut Schütz