NK ☆ India, 2024-08-05 08:07 (94 d 01:26 ago) Posting: # 24128 Views: 1,601 |
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Hello All, Please provide your input for the following, As per the FDA guideline If the pre-dose concentration is ≤ 5 percent of the Cmax value in a subject with a pre-dose plasma concentration, applicants can include the subject’s data without any adjustments in all PK measurements and calculations. We recommend that if the pre-dose value is > 5 percent of the Cmax, applicants drop the subject from all BE study evaluations. My question here is, In a BE study of FDC (or drug with two isomers), If any subject had pre-dose > 5 percent of the Cmax for one drug (or one isomer), What should be followed
NK |
Helmut ★★★ Vienna, Austria, 2024-08-05 10:36 (93 d 22:57 ago) @ NK Posting: # 24129 Views: 1,357 |
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Hi NK, The ICH’s M13A will soon supersed the FDA’s guidance. However, a similar procedure is stated in its Section 2.2.3.3 Carry over. ❝ In a BE study of FDC (or drug with two isomers), If any subject had pre-dose > 5 percent of the Cmax for one drug (or one isomer), What should be followed ❝ 1.Drop the subject from the statistical analysis of both the drug (or both the isomer) or ❝ 2. Drop only for the statistical analysis of a drug (or a isomer) for which the pre-dose observed was > 5 percent of the Cmax and include for other drug (or isomer). The idea of assessing the predose concentrations in higher period(s) is to check whether the washout was sufficiently long. The treatment comparison in the presence of unequal carryover would – unavoidably – be biased and there is no statistical method to adjust for it. For details see this article. In a FDC half lives of components are generally different. In a drug with two isomers the half lives are likely different as well. Therefore, #2 because the washout was long enough for the respective other drug / isomer. — 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 |
Achievwin ★★ US, 2024-08-05 21:08 (93 d 12:25 ago) @ Helmut Posting: # 24134 Views: 1,354 |
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❝ The ICH’s M13A will soon supersed the FDA’s guidance. However, a similar procedure is stated in its Section 2.2.3.3 Carry over. ❝ ❝ The idea of assessing the predose concentrations in higher period(s) is to check whether the washout was sufficiently long. The treatment comparison in the presence of equal/unequal carryover would – unavoidably – be biased and there is no statistical method to adjust for it. Oh my equal/unequal carryover – never ending story |
Helmut ★★★ Vienna, Austria, 2024-08-06 00:39 (93 d 08:54 ago) @ Achievwin Posting: # 24139 Views: 1,300 |
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— 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 |
Ohlbe ★★★ France, 2024-08-08 20:09 (90 d 13:24 ago) @ Helmut Posting: # 24143 Views: 1,203 |
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Dear Helmut, ❝ In a FDC half lives of components are generally different. In a drug with two isomers the half lives are likely different as well. Therefore, #2 because the washout was long enough for the respective other drug / isomer. Yes, but... what if the drug which is still detected induces or inhibits the metabolism of the drug which is no longer detected ? — Regards Ohlbe |
Helmut ★★★ Vienna, Austria, 2024-08-09 10:26 (89 d 23:07 ago) @ Ohlbe Posting: # 24144 Views: 1,186 |
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Dear Ohlbe! ❝ … what if the drug which is still detected induces or inhibits the metabolism of the drug which is no longer detected ? That’s a very good point! One of the prerequisites of a crossover design is that subjects in later period(s) are in the same physiological state than in the drug-naïve first. This is not necessarily always the case – even after a ‘suitable’ washout. Examples:
— 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 |
qualityassurance ★ 2024-08-05 14:48 (93 d 18:45 ago) @ NK Posting: # 24131 Views: 1,328 |
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Hello NK, I completely agree with Helmut. Go with No. 2. Regards, QA |