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Ravi ★ India, 2009-05-15 09:43 (5827 d 13:23 ago) Posting: # 3683 Views: 4,364 |
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Dear All, Is there any regularity guidline about How to access the dose proportionality in a parallel and crossover biostudy? We have just conducted a Parallel, 1 period, three treatment, single dose, investigational pilot study on 18 healthy volunteers. Treatments which were used in this study were (1). Test1 (one 100mg tablet of drug X), (2). Test2 (Two 100mg tablets of drug X), (3). Test3 (No tablet or drug X was given). Group receving Test3 is considered as a control group. Is it possible to access dose proportionality in this type of study. If yes please give me some detail about how to access dose proportionality in this study. Waiting for your valuable suggestion. — Thanks & Regards Ravi Pandey |
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Helmut ★★★   Vienna, Austria, 2009-05-16 02:44 (5826 d 20:22 ago) @ Ravi Posting: # 3684 Views: 3,562 |
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Dear Ravi! ❝ Is there any regularity guidline about How to access the dose proportionality in a parallel and crossover biostudy? As far as I know: no. ❝ Treatments [...] were (1). Test1 (one 100mg tablet of drug X), (2). Test2 (Two 100mg tablets of drug X), (3). Test3 (No tablet or drug X was given). Is it possible to access dose proportionality in this type of study. If your drug is not an endogenous compound, I would expect to see no response at the zero dose level. Most people would use a power model E(Y|x) = a · x bor the log-transformed version log(E(Y|x)) = log(a) + b · log(x)were Y is the untransformed PK-response (AUC, Cmax) and x the dose. Regression is performed with weights set to 1/x. Bad luck if your compound is an exogenous compound (E(0) = 0) - weighting will will not work at x = 0. So you're in the trap of only two dose levels. You cannot distinguish between a linear model and a power model (or any other with two parameters). Furthermore you have no degrees of freedom left, in other words for any assessment of dose proportionality you will need at least three dose levels.For details see one of my lectures. — 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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martin ★★ Austria, 2009-05-16 13:33 (5826 d 09:32 ago) @ Helmut Posting: # 3686 Views: 3,520 |
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dear hs! what do you think about comparing dose-adjusted AUCs? on assumption of dose-proportionality the ratio of dose-adjusted AUCs should be one. in case of more than two dose-levels, application of an adequate stepwise testing procedure (based on the closed testing approach) on dose-adjusted AUCs can help to identify the dose-range where dose-proportionality holds. this approach keeps the familywise error rate at the pre-specified alpha-level which should be more powerful than the application of the bonferroni correction. I am looking forward to your opinion on this topic best regards Martin |
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Helmut ★★★ Vienna, Austria, 2009-05-16 18:24 (5826 d 04:42 ago) @ martin Posting: # 3687 Views: 3,646 |
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Dear Martin! ❝ what do you think about comparing dose-adjusted AUCs? on assumption of dose-proportionality the ratio of dose-adjusted AUCs should be one. Yes, you are right. Actually this is the first model in Chow & Liu's procedure. If BE is demonstrated within conventional limits after dose-normalization, dose linearity (a straight line passing through the origin: E(Y|x) = b·x) is proven.❝ in case of more than two dose-levels, application of an adequate stepwise testing procedure (based on the closed testing approach) on dose-adjusted AUCs can help to identify the dose-range where dose-proportionality holds. this approach keeps the familywise error rate at the pre-specified alpha-level which should be more powerful than the application of the bonferroni correction. Again yes. Since to my knowledge there are no regulatory specifications given for dose-proportionality testing, any approach (if stated in the protocol and agreed upon by IEC and authority) should be acceptable. — 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