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ramesh_7779 ★ 2010-11-25 08:54 (5693 d 13:16 ago) Posting: # 6214 Views: 14,765 |
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Dear All, While performing bioequivalence in Prasugrel, what are all the metabolites to be quantified (As per atricle they have quantified three inactive metabolites like R-95913, R-106583 and R-100932 and one active metabolites R-138727). Please tell me why it is necessary to estimate inactive metabolite in this case. Regards Raja |
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Rajdeep ★ New Delhi, India, 2010-11-25 09:21 (5693 d 12:49 ago) @ ramesh_7779 Posting: # 6217 Views: 13,554 |
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Prasugrel is a pro-drug, so we need to analyze its metabolites. In vivo and ex vivo studies demonstrate that following oral dosing of prasugrel there is a rapid and potent inhibition of ADP-induced platelet activation and aggregation. I guess all the 3 inactive metabolites are to be measured since they are in the plasma within an hour. The active metabolite though present gets converted to the 3rd inactive metabolite. So for a BE study you need to examine the 3 inactive metabolites. For further idea on the same kindly refer this article on Prasugrel pharmacokinetics — Best regards Rajdeep Mukherjee Protocol Developer |
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ramesh_7779 ★ 2010-11-25 11:18 (5693 d 10:52 ago) @ Rajdeep Posting: # 6219 Views: 13,430 |
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Dear Rajdeep, Thanks for the reply. Usually we used to estimate active metabolite only, in case why we are measuring both active and inactive metabolites. Is there any reasons to do so? Rgds Raja |
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Dr_Dan ★★ Germany, 2010-11-25 17:59 (5693 d 04:11 ago) @ ramesh_7779 Posting: # 6231 Views: 13,674 |
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Dear All In an open-label, randomized, four period, 2 x two-way crossover study, we measured the relative bioavailability of tablets containing prasugrel free base compared to prasugrel hydrochloride (EfientTM) both in the presence and in the absence of the proton pump inhibitor lansoprazole was investigated. For this, a respective analytical method for the determination of prasugrel active metabolite was successfully developed and validated. RESULTS: In the absence of lansoprazole, the extent of absorption (AUC) of prasugrel free base is about 8-9% lower, while the rate of absorption (Cmax) after administration of prasugrel free base is about 20% lower when compared to prasugrel hydrochloride. When lansoprazole is used to raise the pH level in the upper gastro-intestinal tract, the relative bioavailability is decreased by about 25% after administration of prasugrel hydrochloride and by about 41% after administration of prasugrel free base. In addition, the peak plasma levels are decreased by about 52% and 72%, respectively (geom. means). CONCLUSION: The relative bioavailability of the prasugrel free base compared to prasugrel hydrochloride, both in the presence and in the absence of the proton pump inhibitor lansoprazole, differs so much that most probably it will not be possible to develop a generic formulation containing prasugrel free base that would be bioequivalent in all aspects to EfientTM. Please contact me for further information Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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ramesh_7779 ★ 2010-11-26 06:20 (5692 d 15:50 ago) @ Dr_Dan Posting: # 6232 Views: 13,473 |
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Dear All, Thanks for the reply. http://www.fda.gov/ohrms/dockets/ac/09/slides/2009-4412s1-01-FDA.pdf As per the reference quoted above i came to know that one should prove bioequivalence for AUC in all level of conversion in presence and absence of PPI's. In absence of PPI, bioequivalence in Cmax for all levels of product conversion, 5% to 70%. With concomitant PPI use, bioinequivalence in Cmax for all levels of product conversion. Is one should carry bioequivalence study with & without PPI's, and tell me the reason why we are measuring inactive and active metabolites. If any other alternate is there suggest me with reference or article. Regards Raja |
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Dr_Dan ★★ Germany, 2010-11-26 10:10 (5692 d 12:00 ago) @ ramesh_7779 Posting: # 6233 Views: 13,355 |
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Dear Raja The parent drug Prasugrel is not detected in plasma since it is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. Peak plasma concentrations (Cmax) of the active metabolite occur approximately 30 minutes after dosing. The following assessment is proposed in the recent EMA guideline CPMP/QWP/EWP/1401/98 Rev. 1: "...Also for inactive prodrugs, demonstration of bioequivalence for parent compound is recommended. The active metabolite does not need to be measured. However, some pro-drugs may have low plasma concentrations and be quickly eliminated resulting in difficulties in demonstrating bioequivalence for parent compound. In this situation it is acceptable to demonstrate bioequivalence for the main active metabolite without measurement of parent compound. In the context of this guideline, a parent compound can be considered to be an inactive pro-drug if it has no or very low contribution to clinical efficacy." If you need reference standard for the active metabolite please contact me. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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ramesh_7779 ★ 2010-11-26 10:28 (5692 d 11:42 ago) @ Dr_Dan Posting: # 6234 Views: 13,344 |
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Dear Dan, Thanks for the information. Rgds Raja |
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sasikala ☆ India, 2010-12-04 16:17 (5684 d 05:52 ago) @ Dr_Dan Posting: # 6268 Views: 13,238 |
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Dear Dr. Dan, We want to perform a comparative bioavailability study of Prasugrel HCl Tablets 10 mg. Kindly advise us, which metabolite has to be measured (Active / Inactive) and also is there any need of adding any stabilizer while collecting the blood. I would very much appreciate Dr., if my queries resolved by you. Thank you Regards sasikala |
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Dr_Dan ★★ Germany, 2010-12-06 09:51 (5682 d 12:19 ago) @ sasikala Posting: # 6269 Views: 13,347 |
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Dear Sasikala as I told Raja bioequivalence should be assessed by measuring the active metabolite. In order to stabilize this metabolite in subjects' samples (as well the Quality Control (QC) samples and calibration standards) blood collection and QC and calibration standards preparation should be done using pre-chilled tubes already pre-prepared containing a 0.5 M 3'-methoxyphenacyl bromide (MPBr) solution in acetonitrile. If you have any further question please do not hesitate to contact me. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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sasikala ☆ India, 2010-12-06 10:56 (5682 d 11:14 ago) (edited on 2010-12-06 12:33) @ Dr_Dan Posting: # 6270 Views: 13,151 |
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muthu ☆ 2010-12-13 11:19 (5675 d 10:51 ago) (edited on 2010-12-13 13:22) @ Dr_Dan Posting: # 6295 Views: 13,100 |
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Dear Dr.Dan, I would like to have the prasugrel Active metabolite standard for our BE studies. Can you help us to get it. Plse send me complete details at [email protected] ALso I have few other queries,
Regards Muthu Edit: 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! [Jaime] |
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marmikpatel_1981 ● 2010-12-10 19:50 (5678 d 02:20 ago) @ ramesh_7779 Posting: # 6290 Views: 13,069 |
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Dear All, I am facing problem detecting prasugrel metabolite using LC-MS/MS. I am not able to generate derivative as suggested in some literature with 2-bromo 3methoxy acetophenone. Please help me or guide me with proper pocedure to get rid of this problem. thanks Marmik Patel |
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Dr_Dan ★★ Germany, 2010-12-14 10:39 (5674 d 11:31 ago) @ marmikpatel_1981 Posting: # 6299 Views: 13,093 |
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Dear all R-138727 is highly unstable in plasma and must be derivatized immediately after blood sampling with 2-bromo-3'-methoxyacetophenone. The determination of R-138727 in plasma is described in several research articles, e.g. N. A. Farid et.al, Rapid Commun. Mass Spectrom. 2007, 21, 169 - 179. If you contact me directly I can offer you the derivatized trans-R-138727MP and the deuterated compound R-138727MP-d3. These compounds R-138727MP and R 138727MP d3 were used as standards to analyse the plasma samples of a comparative bioavailability study with two Prasugrel 10 mg formulations. Do not hesitate to contact me. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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marmikpatel_1981 ● 2010-12-14 19:07 (5674 d 03:03 ago) @ Dr_Dan Posting: # 6303 Views: 13,070 |
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Dear Dr Dan I have purchased R 138727 and not getting derivative as per procedure mentioned in farid et al method also let me know if any special precaution need to be taken. I am not getting the parent ion at 498.5 and also product ion at 348 as mentioned in farid et al publicaiton. please do the needful Thanks Marmik Patel |
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