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olacy ☆ Hungary, 2012-11-07 11:46 (4980 d 02:21 ago) Posting: # 9520 Views: 4,300 |
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Hi, Imagine the following case: The reference product has the following strength: 7 mg, 15 mg and 80 mg The 80 mg reference formulation is breakable. We want to develop an intermediate strength (40 mg) as well as the 80 mg strength. The 40 mg and 80 mg test formulations are not dose proportional. In lack of an appropriate reference strength, can we perform any of the following studies for the marketing authorization of the 40 mg generic formulation? 1 x 40 mg test vs. a half tablet of the 80 mg reference formulation (I don`t think it is feasible) or 2 x 40 mg test vs. 1 x 80 mg reference formulation (I think it may be possible assuming that the pharmacokinetics are linear in the range of 40-80 mg dose) Please note, however, that no information is available regarding the pharmacokinetic linearity between 40 mg and 80 mg strengths. Thanks and best regards, olacy |
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Dr_Dan ★★ Germany, 2012-11-08 11:22 (4979 d 02:46 ago) @ olacy Posting: # 9525 Views: 3,566 |
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Hi olacy I suggest to perform a four way cross-over study with the following treatments: Treatment A): 1 x 80 mg test Treatment B): 1 x 80 mg reference Treatment C): 2 x 40 mg test Treatment D): 1 x 40 mg test You need to demonstrate bioequivalence between Treatment A) and B) and between Treatment C) and B). Treatment D) should be added to assess if the pharmacokinetics are linear in the range of 40-80 mg dose. Assessment of linearity should consider whether differences in dose-adjusted AUC meet a criterion of ± 25%. If the evaluation of treatment D) demonstrates linearity everything is fine, if the evaluation of treatment D) demonstrates, that the drug shows non-linear pharmacokinetics characterised by a more than proportional increase in AUC, you are on the safe side since the bioequivalence study should in general be conducted at the highest strength. If the evaluation of treatment D) demonstrates a less than proportional increase in AUC you have a problem since bioequivalence should in such cases be established both at the highest strength and at the lowest strength. In this situation you should argue with the authority that a study with half tablet of the 80 mg reference formulation is not feasible. I hope this helps Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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ABE1580 ☆ India, 2013-02-14 08:11 (4881 d 05:56 ago) @ Dr_Dan Posting: # 10017 Views: 3,339 |
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Dear Dr Dan, ❝ Assessment of linearity should consider whether differences in dose-adjusted AUC meet a criterion of ± 25%. ❝ ❝ If the evaluation of treatment D) demonstrates linearity everything is fine, if the evaluation of treatment D) demonstrates, that the drug shows non-linear pharmacokinetics characterised by a more than proportional increase in AUC, you are on the safe side since the bioequivalence study should in general be conducted at the highest strength. If the evaluation of treatment D) demonstrates a less than proportional increase in AUC you have a problem since bioequivalence should in such cases be established both at the highest strength and at the lowest strength. How to calculate the dose-adjusted AUC? Does it mean that if AUC for 80 mg strength AUC is 4000 hr*ng/ml. Then for 40 mg it should be 2000 hr*ng/ml. however, we got it around 1300 hr*ng/ml. Then we will set limit as 2000 hr*ng/ml ± 25%. May be a absurd question but I could not able to interpret it properly. Regards, ABE1580 |
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Helmut ★★★   Vienna, Austria, 2013-02-14 13:58 (4881 d 00:09 ago) @ ABE1580 Posting: # 10022 Views: 3,412 |
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Dear ABE, ❝ How to calculate the dose-adjusted AUC? Does it mean that if AUC for 80 mg strength AUC is 4000 hr*ng/ml. Then for 40 mg it should be 2000 hr*ng/ml. however, we got it around 1300 hr*ng/ml. Then we will set limit as 2000 hr*ng/ml ± 25%. Correct: 1500 – 2500 h×ng/mL. Since 1300 < 1500 Dan’s case D) applies. — 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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ABE1580 ☆ India, 2013-02-16 12:21 (4879 d 01:47 ago) @ Helmut Posting: # 10040 Views: 3,362 |
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Dear Helmut, Thank you.... Regards, ABE1580 |
Ing. Helmut Schütz