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ioanam ★ Romania, 2010-08-10 12:42 (5781 d 12:47 ago) Posting: # 5752 Views: 10,557 |
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Dear all, I need your help to clarify some results in a bioequivalence study for clopidogrel. We have found values for plasma concentrations for clopidogrel more than 10 fold higher than those reported in literature. The study was performed in healthy male and female subjects in standard fasting state. Even clopidogrel is a highly variable drug, I can't explain these high values. It is really possible to have peak concentrations of almost 20 pg/ml for clopidogrel? I don't think so. Am I right? Thank you, Ioanam |
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Dr_Dan ★★ Germany, 2010-08-10 13:21 (5781 d 12:08 ago) @ ioanam Posting: # 5753 Views: 9,548 |
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Dear Ioanam Please check your analytical method. You will certainly find out that there is a back conversion of the inactive metabolite (concentration up to 5000 fold increased to parent drug) to clopidogrel. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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ioanam ★ Romania, 2010-08-10 13:28 (5781 d 12:01 ago) @ Dr_Dan Posting: # 5754 Views: 9,564 |
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We will do this. Thank you |
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ioanam ★ Romania, 2010-08-10 13:43 (5781 d 11:46 ago) @ Dr_Dan Posting: # 5755 Views: 9,503 |
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In the analytical method, to avoid back - conversion, methanol was not used. It was changed with acetonitrile. There are other conditions to produce back - conversion of clopidogrel? Thank you, ioanam |
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Ohlbe ★★★ France, 2010-08-10 14:17 (5781 d 11:12 ago) @ ioanam Posting: # 5757 Views: 9,625 |
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Dear Ioanam, Back-conversion of clopidogrel metabolites is known, but still not fully understood and explained. Is is indeed known that methanol (during the sample extraction, or in the mobile phase) can cause this back-conversion, but other factors may be involved too. I think there were also reports of back-conversion in the absence of methanol, when using some specific solid phase extraction columns. In fact it is not even sure which metabolite is back converted. It was initially said to be clopidogrel carboxyacid, but a poster at ASMS 2010 says it is due to transesterification of clopidogrel acyl glucuronide. Fabio Garofolo and colleagues from Algorithme Pharma made several communications and posters on clopidogrel and back-conversion. Have a look on Internet. Regarding your current study what I would suggest if you have enough sample volume would be to try incurred sample re-analysis. If you see wide differences between your first and second result you'll be quite sure you have a back-conversion problem. — Regards Ohlbe |
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ioanam ★ Romania, 2010-08-10 16:13 (5781 d 09:16 ago) @ ioanam Posting: # 5761 Views: 9,416 |
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Dear all, I need to make an erratum for the first message. The maximum values found for clopidogrel were almost 20 ng/ml (not pg/ml). A value of 1990 pg/ml is in accordance with the published data in literature. In my case, the mean value for Cmax was much higher than those reported in other studies. More than that, the values of individual peak plasma concentrations ranged between 0.27 to 18.89 ng/ml (18890.0 pg/ml) for both test and reference products. I can't find a scientific explanation for these differences between results. Thank you, Ioanam |
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Ohlbe ★★★ France, 2010-08-10 16:59 (5781 d 08:30 ago) @ ioanam Posting: # 5762 Views: 9,446 |
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Dear Ioanam, I misread your first message, I thought you had a mean Cmax of 20 ng/ml, not a highest Cmax with that value. What mean value do you get for Cmax ? — Regards Ohlbe |
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ioanam ★ Romania, 2010-08-10 17:17 (5781 d 08:12 ago) @ Ohlbe Posting: # 5763 Views: 9,452 |
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Dear Ohlbe, I'm sorry that I did not present very clear my question. The mean value obtained in the study is around 5 - 6 ng/ml for both products. Statistical results showed a T/R ratio of almost 1.0, but the study failed for Cmax (using 80 - 125%) and EMA does not approve to wide 90% IC for clopidogrel. I still can't explain those increased values for Cmax. I have to find if there is a mistake in this study, where to find it. Kindest regards, Ioanam |
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Ohlbe ★★★ France, 2010-08-10 18:12 (5781 d 07:16 ago) @ ioanam Posting: # 5764 Views: 9,655 |
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Dear Ioanam, ❝ The mean value obtained in the study is around 5 - 6 ng/ml for both products. What was the dose in your study ? 75 mg, 150 mg ? Look at the data in EPAR on EMA's web site (values for the reference product):
— Regards Ohlbe |
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ioanam ★ Romania, 2010-08-10 20:34 (5781 d 04:54 ago) @ Ohlbe Posting: # 5767 Views: 9,502 |
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Dear Ohlbe we have results from 63 subjects; the dose administered was 150 mg. Thank you for the EPARs. I already compared our results with those reported there. But I have other reports from other studies using the same dose (150 mg) and the results were lower than ours (in general around 2 - 3 ng/ml). In this study, the between - subject variability is around 50% (?). Even clopidogrel is a HVD, can I have such differences in the same subjects, eq: - almost 6 ng/ml (for one formulation) compared to 15 ng/ml (the other formulation) - almost 6 ng/ml compared to almost 19 ng/ml or - almost 3 ng/ml compared to almost 18 ng/ml? These differences seems to be to high (for me). Perhaps I am wrong. I don't know. Regards, ioanam |
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Dr_Dan ★★ Germany, 2010-08-11 11:24 (5780 d 14:05 ago) @ ioanam Posting: # 5768 Views: 9,495 |
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Dear Ioanam No, you are not wrong! In my last Clopidogrel study (75 mg single dose replicate design) I had several subjects showing great differences between treatments. One subject under reference: first treatment 2963 pg/ml, second treatment: 399 pg/ml → factor >7. Onother subject also under reference: first treatment 354 pg/ml, second treatment: 9227 pg/ml → factor 30! (o.k. this was the most extreme…) Clopidogrel is a lausy variable drug. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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ioanam ★ Romania, 2010-08-11 13:08 (5780 d 12:20 ago) @ Dr_Dan Posting: # 5770 Views: 9,379 |
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Dear Dr_Dan and dear all, Thank you for your responses. Yes. There are differences. But in your study, you had values of 2 ng/ml. And here, for 150 mg administered, we had 18 ng/ml - for reference. And I did not find anywhere in literature such high values and after reviewing the analytical methodology I didn't find any explanation for a possible back - conversion. I have also other question. There are any important differences between clopidogrel -d3, -d4 or -d6 used as internal standard regarding the final results? Thank you for your support, Ioanam |
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Ohlbe ★★★ France, 2010-10-05 02:06 (5725 d 23:23 ago) @ ioanam Posting: # 5994 Views: 9,567 |
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Dear Ioanam, In case you are still working on this topic: there is a very nice paper in press in the Journal of Chromatography B on clopidogrel back-conversion. Development and Validation of an HPLC-MS/MS Method to Determine Clopidogrel in Human Plasma; Use of Incurred Samples to Test Back-Conversion Luigi Silvestro, Mihaela Cristina Gheorghe, Isabela Tarcomnicu, Silviu Savu, Simona Rizea Savu, Adriana Iordachescu and Constanta Dulea doi:10.1016/j.jchromb.2010.09.022 ❝ I have also other question. ❝ There are any important differences between clopidogrel -d3, -d4 or -d6 used as internal standard regarding the final results? In this paper they are using -d3, but with the 37Cl isotope for the IS instead of the 35Cl isotope for the analyte. This is quite smart: they were having cross-talk with -d3 when using the same Cl isotope, but no longer with the different isotope, without the need for an increase in the number of deuterium in the IS which could introduce or increase a difference in retention times between the analyte and the IS. — Regards Ohlbe |
Ing. Helmut Schütz