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ioanam ★ Romania, 2009-05-06 19:12 (5847 d 18:51 ago) Posting: # 3653 Views: 8,544 |
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Dear All, Thank you for your help every time I am asking it, since I am new in this area. I have another uncertainty. In a bioequivalence study (using healthy subjects) we found a mean elimination half – life (for test and also for reference) more than 5 times than the values described in the literature. Can you offer me a possible explanation for this result? Thank you very much, Ioanam |
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Ohlbe ★★★ France, 2009-05-06 19:54 (5847 d 18:09 ago) @ ioanam Posting: # 3654 Views: 7,036 |
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Dear Ioanam, ❝ Can you offer me a possible explanation for this result? There are several possible explanations, for instance: - you have a lower LLOQ than what was used for the published studies, and a drug with a multicompartmental PK. You manage to see the real terminal elimination phase, while published studies did not, and only saw an "intermediate" half-life (I'm not sure what it should be called, sorry) or just the distribution phase. The PK profiles on a semilog scale will tell you more. If you obviously have a monocompartmental profile, this will not be the correct explanation. - your bioanalytical method is not reliable with low concentrations, or you have an interference of some kind, possibly with a metabolite  .Regards Ohlbe |
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ioanam ★ Romania, 2009-05-06 20:44 (5847 d 17:19 ago) @ ioanam Posting: # 3655 Views: 7,166 |
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Thank you for your response. Unfortunately, there are several problems: 1. the substance is already a prodrug and we investigated the metabolite concentrations. 2. we used a monocompartmental model for calculation of pharmacokinetic parameters 3. the LLOQ is in the same range as values presented in literature. I don't know what to say. Ioanam |
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ElMaestro ★★★ Denmark, 2009-05-06 21:13 (5847 d 16:50 ago) @ ioanam Posting: # 3656 Views: 7,047 |
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Hi, 1. Could genetic/regional differences account for this? If the drug for instance is eliminated by the liver (CYP's etc) then some differences might be expected between populations of different genetic makeup. For example, alcohol is burned less efficintly by certain populations in Asia than in e.g. Europeans. 2. Could other population differences account for it (were the references generated with patients)? Best regards EM. |
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ioanam ★ Romania, 2009-05-06 21:43 (5847 d 16:20 ago) @ ElMaestro Posting: # 3657 Views: 7,062 |
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All subjects analyzed were Caucasian healthy subjects, so we can exclude this hypothesis. I didn't find in literature references about genetic differences of its metabolism. Although we found this discrepancy in half life values reported to the literature data, statistical analysis did not reveal significant differences between treatments. Do you consider that our results may be a reason to concern us in case of submission in EU? Regards, Ioanam |
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ElMaestro ★★★ Denmark, 2009-05-06 23:54 (5847 d 14:10 ago) @ ioanam Posting: # 3658 Views: 7,053 |
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Hi ioanam, ❝ Do you consider that our results may be a reason to concern us in case of ❝ submission in EU? While I understand your worry, I would not think this would be too much of a problem. After all, if your trial is conducted well and you reported the data in a proper manner then you have done exactly what you were supposed to. In addtion, BE is just about comparing two formulations, not really about characterising the PK of the drug in either of them. Oh I forgot to mention another thing: Often it is very unclear how PK-characteristics for reference drugs have been produced, and even if it is known it can be difficult to judge how different the data will seem compared to data analysed the way it is done in a BE-study. In your study have perhaps looked at some terminal three or four data points on the (log C vs time)-plot and calculated t½. Has the applicant done the same? Used an n-compartmental model, fitted using some weighting scheme, using least squares or ... ? Weighting can infuence the estimate of t½ quie a bit, have a look here Best regards EM. |
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