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Dr Andrew Leary ★ Ireland, 2010-05-21 12:21 (5881 d 06:24 ago) Posting: # 5363 Views: 3,680 |
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Hello Helmut Good to see you in Ljubljana. As I've said before, keep fighting the good fight! I've been asked to design a BE study for an IV formulation. It is expected that proof of BE will be required because of differences in how the formulation has been put together compared to reference. In my view (based on NO experience!), IV administration (in this case, a 1-hour infusion) should ensure very low intra-subject CVs for Cmax and AUC because BA will be 100% in all cases. This should allow for a small study (perhaps only 12 subjects) if all the other usual assumptions apply. Do you concur, or is there something I'm missing? Kind regards Andrew |
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Helmut ★★★   Vienna, Austria, 2010-05-21 14:56 (5881 d 03:49 ago) @ Dr Andrew Leary Posting: # 5364 Views: 2,983 |
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Hi Andrew! ❝ Good to see you in Ljubljana. THX, was a nice meeting. ❝ As I've said before, keep fighting the good fight! Who's fighting? I would call it discourse.  ❝ It is expected that proof of BE will be required because of differences in ❝ how the formulation has been put together compared to reference. What do you actually mean by "putting together"? Are you referring to one of the special conditions stated in Appendix II of the guideline? ❝ In my view (based on NO experience!), IV administration (in this case, a ❝ 1-hour infusion) should ensure very low intra-subject CVs for Cmax and AUC ❝ because BA will be 100% in all cases. This should allow for a small study ❝ (perhaps only 12 subjects) if all the other usual assumptions apply. ❝ Do you concur, or is there something I'm missing? Tricky. You are right that F will be 1 (by definition), but what if the drug itself (not the formulation!) is highly variable based on variable clearance? One of the assumptions in BE are constant clearances (no between occasion changes). If clearances vary, you will see differing PK metrics not caused by the formulations, but by varying elimination... I would go with a sequential design in that case. Start the first stage in a sample size large enough to get twelve subjects (the minimum in the EU) after eventual drop-outs. — 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, 2010-05-21 15:26 (5881 d 03:19 ago) @ Helmut Posting: # 5365 Views: 2,961 |
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Many thanks for this, Helmut! ❝ What do you actually mean by "putting together"? Are you referring ❝ to one of the special conditions stated in Appendix II of the ❝ guideline? I know little about pharmaceutics, but I think that the new formulation involves some sort of cyclodextran, which I guess means that the line "if any excipients interact with the drug substance (e.g. complex formation), or otherwise affect the disposition of the drug substance" in Appendix II would apply. ❝ I would go with a sequential design in that case. Start the first stage in ❝ a sample size large enough to get twelve subjects (the minimum in the EU) ❝ after eventual drop-outs. Very clever. I expect we'll see increased use of the sequential design in the years to come. I'll have my statistician get intimate / cosy with Potvin. Have a good weekend! |
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Helmut ★★★ Vienna, Austria, 2010-05-21 15:36 (5881 d 03:09 ago) @ Dr Andrew Leary Posting: # 5366 Views: 2,958 |
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Dear Andrew! ❝ I know little about pharmaceutics, but I think that the new formulation ❝ involves some sort of cyclodextran, which I guess means that the line "if ❝ any excipients interact with the drug substance (e.g. complex formation), ❝ or otherwise affect the disposition of the drug substance" in Appendix II ❝ would apply. Probably to likely: yes. ❝ I expect we'll see increased use of the sequential design in the years to ❝ come. Me too. I made it my standard for 2×2 studies, unless I have a lot of data from previous studies beforehand. ❝ I'll have my statistician get intimate / cosy with Potvin. Do so. It's not complicated at all. Don't forget to modify the statistical model if you proceeded to stage 2 (see here). — 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