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BarbaraM ☆ Greece, 2014-08-07 16:40 (4337 d 15:45 ago) Posting: # 13347 Views: 10,879 |
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Dear Group, I would like to have your views on the below issue. A drug as tablets of 500 mg and 1000 mg is to be dosed in real life by calculating the dose per kg body weight (25 mg/kg). e.g. a patient of 60 kg will receive a single dose of 1500 mg; that is he will get 1 tab of 1000 mg and 1 tab of 500 mg a patient of 80 kg will receive a single does of 2000 mg; that is he will get 2 tabs of 1000 mg (or 4 tabs of 500 mg). how should the healthy subjects be dosed in a BE study? should they be dosed by taking into account their body weight (as above) or regardless of their body weight take the 1000 mg tab? Thanking you in advance for your feedback. |
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ElMaestro ★★★ Denmark, 2014-08-07 17:01 (4337 d 15:24 ago) @ BarbaraM Posting: # 13348 Views: 9,593 |
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Hi BarbaraM, ❝ how should the healthy subjects be dosed in a BE study? should they be dosed by taking into account their body weight (as above) or regardless of their body weight take the 1000 mg tab? As far as I know in practice this should give the same evaluation so it is your choice unless there is a product-specific guidance or safety concerns merits one solution over the other. I would opt for the simplest solution - i.e. fixed dose. Simplest solution often means less variation. You may add some considerations about linearity (proportionality). — Pass or fail! ElMaestro |
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Helmut ★★★   Vienna, Austria, 2014-08-07 17:12 (4337 d 15:14 ago) @ BarbaraM Posting: # 13349 Views: 9,710 |
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Γειά σου Βαρβάρα! ❝ how should the healthy subjects be dosed in a BE study? should they be dosed by taking into account their body weight […] or regardless of their body weight take the 1000 mg tab? When you talk about healthy subjects I guess you are referring to bioequivalence? See EMA’s definition: Two medicinal products containing the same active substance are considered bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and their bioavailabilities (rate and extent) after administration in the same molar dose lie within acceptable predefined limits. (my emphasis)EMA wants BE to be demonstrated for the highest strength (under certain conditions BE-studies of lower strengths can be waived).
— 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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BarbaraM ☆ Greece, 2014-08-07 18:31 (4337 d 13:54 ago) @ Helmut Posting: # 13350 Views: 9,668 |
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Hi! thank you both for the quick feedback and the Greek salut  .Indeed I'm referring to a standard 2-way cross over BE. My concern rises from the fact that if we dose 1 tab of 1000 mg (highest strength) then depending on the subject's body weight this will result in doses much less than the 25 mg/kg that is specified in the SmPC (e.g. for the 60 kg subject would result in ~17 mg/kg) and I assume that this will result in a Cmax and AUC less than the SmPC proposes. It would be as if we had 2 strength of a product and we were to dose the smallest strength, instead of the highest as the EMA guideline proposes to be the most discriminatory case. What do you think? Does this make any sense? |
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ElMaestro ★★★ Denmark, 2014-08-07 19:42 (4337 d 12:43 ago) @ BarbaraM Posting: # 13351 Views: 9,544 |
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Hi BarbaraM, ❝ Indeed I'm referring to a standard 2-way cross over BE. My concern rises from the fact that if we dose 1 tab of 1000 mg (highest strength) then depending on the subject's body weight this will result in doses much less than the 25 mg/kg that is specified in the SmPC (e.g. for the 60 kg subject would result in ~17 mg/kg) and I assume that this will result in a Cmax and AUC less than the SmPC proposes. Note that dosing per SPC is not a goal in itself (at least not for EU submissions). ❝ It would be as if we had 2 strength of a product and we were to dose the smallest strength, instead of the highest as the EMA guideline proposes to be the most discriminatory case. ❝ What do you think? Does this make any sense? Could be succesful. At least the low strenght will be approvable if the study turns out equivalent. If you can argue less-than-proportional kinetics or a safety concern then you may have an additional good argument. — Pass or fail! ElMaestro |
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Dr_Dan ★★ Germany, 2014-08-11 02:10 (4334 d 06:15 ago) @ BarbaraM Posting: # 13360 Views: 9,448 |
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Dear BarbaraM First of all one question: Do you need to dose patients? I guess this is the case, right? Bad luck.... You can not mix two strenghts (500 mg and 1000 mg = two formulations) for the assessment of bioequivalence. I would go for a scientific advice proposing the execution of the study with the lower strength. Kind regards Dr_Dan — Kind regards and have a nice day Dr_Dan |
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Helmut ★★★ Vienna, Austria, 2014-08-11 13:02 (4333 d 19:23 ago) @ Dr_Dan Posting: # 13362 Views: 9,474 |
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Dear Dr Dan, ❝ First of all one question: Do you need to dose patients? I guess this is the case, right? I don’t think so since Barabara wrote in her original post: ❝ ❝ A drug […] is to be dosed in real life by calculating the dose per kg body weight […]. ❝ ❝ how should the healthy subjects be dosed in a BE study? @Barbara: Can you clarify please? — 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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luvblooms ★★ India, 2014-08-11 08:56 (4333 d 23:29 ago) @ BarbaraM Posting: # 13361 Views: 9,412 |
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Dear Barbara ❝ how should the healthy subjects be dosed in a BE study? should they be dosed by taking into account their body weight (as above) or regardless of their body weight take the 1000 mg tab? You can Check the EMA BE requirment for Capecitabine. For Capectiabine Standard and reduced dose calculations according to body surface area for starting doses of capecitabine of 1250mg/m2 and 1000mg/m2, respectively but for BE study Strength to be used is 500 mg because it is the highest strength. Hope this will help. — ~A happy Soul~ |
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Helmut ★★★ Vienna, Austria, 2014-08-11 13:14 (4333 d 19:11 ago) @ luvblooms Posting: # 13363 Views: 9,415 |
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Hi Luv, ❝ You can Check the EMA BE requirment for Capecitabine. I think that EMA’s draft guidance can easily be misinterpreted (see my remarks at the end of this post). Maybe the guidance’s wording is just ambiguous. The 500 mg strength is OK, but should not be interpreted as the suitable dose – which should still be calculated according to the common posology. — 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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luvblooms ★★ India, 2014-08-12 08:28 (4332 d 23:57 ago) @ Helmut Posting: # 13364 Views: 9,377 |
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Hi Helmut ❝ I think that EMA’s draft guidance can easily be misinterpreted (see my remarks at the end of this post). Maybe the guidance’s wording is just ambiguous. The 500 mg strength is OK, but should not be interpreted as the suitable dose – which should still be calculated according to the common posology. Totally agreed to the point raised by you. Also the study has to be done in patients thus using just 500 mg (where as the dose based on BSA lies in 1500-2500 mg) is also not ethically right. We have already asked for clarification on the same from EMEA. Lets see if we can get a reply. IF the study has to be done on healthy volunteers (after regulatory consultation) using 500 mg should be ok. Remember Imatinib guidance — ~A happy Soul~ |
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Helmut ★★★ Vienna, Austria, 2014-08-12 14:23 (4332 d 18:02 ago) @ luvblooms Posting: # 13369 Views: 9,370 |
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Hi Luv, ❝ […] the study has to be done in patients thus using just 500 mg (where as the dose based on BSA lies in 1500-2500 mg) is also not ethically right. We have already asked for clarification on the same from EMEA. Lets see if we can get a reply. Did you also send a comment on the draft guidance to the EMA (as I did)? ❝ IF the study has to be done on healthy volunteers (after regulatory consultation) using 500 mg should be ok. Yes. ❝ Remember Imatinib guidance I do.  — 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 |
Ing. Helmut Schütz