Log in
Register|
rahul dixit ☆ 2011-01-14 10:00 (5637 d 13:35 ago) Posting: # 6414 Views: 6,737 |
|
|
Dear All, we had worked on angiotensin receptor antagonist. The molecule has inherent variability. It has bioavailability of 13 % and also has a regiospecific absorption (from duodenum to jejunum). We carried study where we compared two test formulations with the innovator. The study was completed in three period. The study was marginally failed. when the data was analysed, it was observed that the varibaility in period three was on higher side as compared to period 1 and 2. The higher variability in period three is irrespective of the formulations dosed to the healthy volunteers. The variability in Cmax is given below. Formulations % CV values TestProduct1 TestProduct2 Reference The 90 % CI values are given below Cmax AUC 0-t AUC 0-inf The dissolution profiles of the molecule are carried out in multi pH media (0.1 N HCl, pH 4.5, pH 6.8 and pH7.4) The molecule is insoluble at pH 4.5 (2-3 % dissolution) while it is sparingly soluble in acid and has good solubility above pH 6.0. The dissolution profile of the in house test product is matching in all media with that of innovator. Considering the above results, we are unable to understand the causes of failure in BE study. Kindly suggest Regards Rahul Edit: Please don't use tabs in posts - use BBCodes instead. [Helmut] |
|
Dr_Dan ★★ Germany, 2011-01-14 15:57 (5637 d 07:38 ago) @ rahul dixit Posting: # 6416 Views: 5,676 |
|
|
Dear Rahul According to your table the variability is less in period III than in the first two periods. Did you mixed up periods and treatments? What kind of variability do you present, inter- or intra-subject variability? Have you performed any outlier detection tests? However, regarding the 90% CI it will become difficult to demonstrate bioequivalence with your formulation..... How many subjects were enrolled into the study? Please provide more information. Looking forward to your reply Dan — Kind regards and have a nice day Dr_Dan |
|
rahul dixit ☆ 2011-01-15 08:53 (5636 d 14:42 ago) (edited on 2011-01-15 12:57) @ Dr_Dan Posting: # 6419 Views: 5,556 |
|
|
Dear sir, You are right. While doing the formatting I mixed with the periods. I am sorry. The corrected values are given below. The number of volunteers used in the study were 30. % Inter subject CV values Period 1 Period 2 Period 3Thanks and Best regards Rahul Edit: Table formatted using BBCodes. Full quote removed. Please delete anything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Ohlbe] |
|
Dr_Dan ★★ Germany, 2011-01-17 15:59 (5634 d 07:36 ago) @ rahul dixit Posting: # 6430 Views: 5,483 |
|
|
Dear Rahul Obviously there is a period effect. Although the sample size seems to be too low for an adequate BE assessment (high intra-subject variability assumed from wide 90% CI) the data from period 3 show consistently higher values. It is improbable that outliers occured only in period 3 and for all treatments in the same way. Something went terribly wrong in period 3, e.g. administration in the fed state while in period 1 and 2 treatments were administerd in the fasted state? I suggest to perform a study audit to find the reason for the deviation in period 3. Nevertheless as I already mentioned your formulation is far away from beeing bioequivalent I hope this helps Kind regards Dan — Kind regards and have a nice day Dr_Dan |
|
rahul dixit ☆ 2011-01-18 07:00 (5633 d 16:35 ago) @ Dr_Dan Posting: # 6436 Views: 5,525 |
|
|
Dear Sir, Thanks a lot. We could not find the root cause of the variability. Is matching a dissolution profile in multi pH media with innovator helpful to achieve the bioequivalence ? With BCS class IV molecules with site specific absorption, what will be the criteria to achive the bioequivalence? Are there any other tools other than dissolution study to identify the right test formulation to carry out the BE study? What are the critical things which needs to be added in the study protocol to reduce the variability? is partial replicate design helpful for class IV molecules? Regards Rahul |
|
Dr_Dan ★★ Germany, 2011-01-18 10:40 (5633 d 12:55 ago) @ rahul dixit Posting: # 6438 Views: 5,528 |
|
|
Dear Rahul ❝ Is matching a dissolution profile in multi pH media with innovator helpful ❝ to achieve the bioequivalence ? If in vitro matching dissolution profiles would automatically lead to in vivo bioequivalence you would not need a BE study. Sometimes your formulation has a different dissolution profile but you are bioequivalent. According to CPMP/QWP/EWP/1401/98 Rev. 1: "In the event that the results of comparative in vitro dissolution of the biobatches do not reflect bioequivalence as demonstrated in vivo the latter prevails." So it is just a hint. ❝ With BCS class IV molecules with site specific absorption, what will be ❝ the criteria to achive the bioequivalence? Good question. If you can answer this then you will become rich and famous.  ❝ Are there any other tools other than dissolution study to identify the ❝ right test formulation to carry out the BE study? You can try biorelevant media (FaSSIF/FeSSIF (fasted/fed state simulating intestinal fluid containing bile salt/lecithin) = media for mimicking the gastric environment), investigate the physicochemical characterisation of APIs, the influence of excipients, the influence of particle size, the influence of aggregation/wetting, sink conditions etc. ❝ What are the critical things which needs to be added in the study protocol ❝ to reduce the variability? Standardization, standardization, standardization. Each period should be exactly be the same as the previous and the following. The treatments must be identical (only exception: study drug). It is not only a question of study protocol preparation but more a question of CRO staff performance. ❝ is partial replicate design helpful for class IV molecules? It is helpful for highly variable drugs, not only for class IV molecules. You need a replicate design in order to widen the acceptance range for Cmax. I personally prefer the full replicate design since you get more T/R comparisons. Regards Dan — Kind regards and have a nice day Dr_Dan |
|
Helmut ★★★   Vienna, Austria, 2011-01-18 12:11 (5633 d 11:24 ago) @ Dr_Dan Posting: # 6440 Views: 5,649 |
|
|
Dear Dan! ❝ According to CPMP/QWP/EWP/1401/98 Rev. 1: "In the event that the results of ❝ comparative in vitro dissolution of the biobatches do not reflect bioequivalence ❝ as demonstrated in vivo the latter prevails." The next sentence is: "However, possible reasons for the discrepancy should be addressed and justified." (my emphases) Justify:
 — 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 |
|
Dr_Dan ★★ Germany, 2011-01-18 12:55 (5633 d 10:40 ago) @ Helmut Posting: # 6442 Views: 5,577 |
|
|
Hi Helmut, you are right. All I wanted to say is that regarding bioequivalence you can not (only) rely on your dissolution results. At the moment Rahul has a formulation showing comparable dissolution but no bioequivalence. Maybe his dissolution method does not discriminate sufficiently? It is a poorly soluble drug with low bioavailability. These drugs are a nightmare even if you just copy the reference formulation. Once you have a bioequivalent product it is IMHO easier to find reasons for the discrepancy than the other way round. Dan — Kind regards and have a nice day Dr_Dan |
|
Helmut ★★★ Vienna, Austria, 2011-01-18 16:23 (5633 d 07:12 ago) @ Dr_Dan Posting: # 6443 Views: 5,452 |
|
|
Dear Dan! ❝ you are right. As are you. ❝ Once you have a bioequivalent product it is IMHO easier to find reasons for ❝ the discrepancy than the other way round. Exactly. Jean-Michel Cardot (one of the preachers of IVVC), always tries to break the news to noobs: Start in vivo! — 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 |
|
rahul dixit ☆ 2011-01-19 06:14 (5632 d 17:21 ago) @ Helmut Posting: # 6444 Views: 5,502 |
|
|
Dear Sir, I have read about posture restriction which is added in study protocol to reduce the variability. Dose it really help to reduce the variability in case of highly variable drug? If yes, how many hours, a posture restriction is to be kept? Regards Rahul |
|
Dr_Dan ★★ Germany, 2011-01-19 11:07 (5632 d 12:29 ago) @ rahul dixit Posting: # 6447 Views: 5,398 |
|
|
Dear Rahul posture restriction is common to reduce the variability. You should always add some information regarding posture post dose in the study protocol. If the subjects should lay down or sit and the time needed depend on the drug (safety, tmax, place of absorption etc.). Kind regards Dan — Kind regards and have a nice day Dr_Dan |
|
Helmut ★★★ Vienna, Austria, 2011-01-19 11:52 (5632 d 11:43 ago) @ rahul dixit Posting: # 6448 Views: 5,462 |
|
|
Dear Rahul! ❝ [...] posture restriction [...] to reduce the variability C Queckenberg and U Fuhr — 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 |
|
rahul dixit ☆ 2011-01-19 14:28 (5632 d 09:07 ago) @ Helmut Posting: # 6450 Views: 5,324 |
|
|
Thanks a lot Regards Rahul |
Ing. Helmut Schütz