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Dr_Dan ★★ Germany, 2011-02-17 11:34 (5199 d 05:41 ago) Posting: # 6641 Views: 10,767 |
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Dear all There is a wide experience that for many drugs the pharmacokinetics in women differ from those in men and these differences may be explained for example by differences in body weight. Since individualization of drug dosage should be based on therapeutic response gender differences in some pharmacokinetic parameters have no implications for therapy. For testing generic drug products these gender differences do not matter since the objective of a bioequivalence study is, however, not the investigation of the pharmacokinetics of the drug entities itself, but the comparison of the pharmacokinetic profiles of galenic preparations. Bioequivalence is generally recommended to be examined in subjects of both sexes. Based on the assumption that an interaction between galenics and sex of the subject is highly unlikely, the statistical evaluation of a BE study include the whole study population and does not distinguish between different subpopulations (i.e. males and females). There is a wide experience that two formulations that were bioequivalent in one study population will also be bioequivalent in other populations [Rhodes CT: Generic substitution: Does interchangeability mean equality of all functional relevant attributes? Clin Res Reg Affairs (1995), 12(4): 267-272]. Usually a cross-over design is used which is the most powerful design for a bioavailability study since it removes the inter-subject variability (gender differences in pharmacokinetics) from the comparison of average bioavailability between the formulations. This was the stand of my knowledge until yesterday. We performed a BE study with borderline results in Cmax. The study was well powered and the ratio between males and females was almost equal so we decided to evaluate both sexes separately (with a power of ca. 80% each). The result was striking: whereas the comparison Test vs Reference in females clearly demonstrated bioequivalence within the acceptance range of 80-125%, the 90% CI in men was in great parts (including the point estimator) outside the acceptance range. There was only a very small overlap in CI between men and women. In conclusion there is a clear interaction between galenics and sex of the subject. Do you agree? Have you ever seen such a phenomenon and what could be the explanation? I am looking forward to your reply. Kind regards Dan Edit: Category changed. [Helmut] — Kind regards and have a nice day Dr_Dan |
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ElMaestro ★★★ Denmark, 2011-02-17 14:54 (5199 d 02:21 ago) (edited on 2011-02-17 16:02) @ Dr_Dan Posting: # 6644 Views: 9,207 |
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Dear Dr_Dan, wow - this is a great story and I'd love to learn more. Stories like this have great potential. Could you tell what the intra-subject CV's (and perhaps T/Rs, but less important) in the two populations were? After all, this could be just a coincidence although it certainly sounds like you are on to an unusual phenomenon here. — Pass or fail! ElMaestro |
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Dr_Dan ★★ Germany, 2011-02-17 16:09 (5199 d 01:06 ago) @ ElMaestro Posting: # 6645 Views: 9,089 |
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Hi Anders when you look at the data I guess you will agree that the result is not caused by outliers. ANOVA CV% whole population: 15.3 males only: 15.1 females only: 14.7 inter-subject CV% whole population: T: 30, R: 33 males only: T: 33, R: 33 females only: T: 27, R: 28 Very consistent data. Only if you look at the T/R ratio it becomes very strange: whole population: 117.0 males only: 125.5 females only: 109.4 Due to patent circumvention strategies the Test formulation differs in qualitative and quantitative composition from the Reference. I hope these information are sufficient for a further discussion. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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ElMaestro ★★★ Denmark, 2011-02-17 16:44 (5199 d 00:31 ago) @ Dr_Dan Posting: # 6646 Views: 8,986 |
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Dear Dr_Dan, ❝ when you look at the data I guess you will agree that the result is not caused by outliers. Agree, these data look consistent; a potential difference might exist. I need to scratch the back of my head a little over this... Gender × drug in PROC GLM, anyone? |
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Dr_Dan ★★ Germany, 2011-03-11 16:24 (5177 d 00:51 ago) @ ElMaestro Posting: # 6751 Views: 8,774 |
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Dear ElMaestro dear all I just evaluated the second study with the same compound/dose/nearly identical formulation. Evaluation with the whole study population => bioequivalent Subgroups: males => AUC bioequivalent females => AUC bioequivalent 90% confidence intervals for AUC for males and females have no overlap (99-121 vs 83-95) 90% confidence intervals for Cmax for males and females congruent. Is this just a statistical artefact? Looking forward to your reply Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Helmut ★★★   Vienna, Austria, 2011-03-11 16:32 (5177 d 00:43 ago) @ Dr_Dan Posting: # 6752 Views: 8,794 |
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Dear Dan, your fascinating story continues…  If you want, you can send me your data off-list – including bodyweights. I don’t promise anything, but I’m really curious to see what’s going on here. — 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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ElMaestro ★★★ Denmark, 2011-03-11 17:37 (5176 d 23:38 ago) @ Dr_Dan Posting: # 6753 Views: 8,758 |
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Dear Dan, ❝ Is this just a statistical artefact? Well, that can't be ruled out but you make a good case why it isn't. ❝ Looking forward to your reply I do not have an explanation. I am thinking into coating or other excipients but have not heard of any such things having gender specificity. In principle a story like this deserves publication, but I would not be surprised if originator companies would use it against the generic industry in an attempt to make life difficult. Another thing: Sometimes males and females are separated (dosing, sleeping, meals etc) at CROs. Do you know if this was the case in your studies? I think I would look into this aspect; after all, subtle differences in habits and the fact that BE studies are open-label could play a role, although I will not speculate into exactly how this might be with the present knowledge. And oh please, include me on the recipient list for the data  — Pass or fail! ElMaestro |
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Dr_Dan ★★ Germany, 2011-03-14 10:20 (5174 d 06:55 ago) @ ElMaestro Posting: # 6758 Views: 8,937 |
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Dear ElMaestro males and females were not separated. Females were dosed at the same time together with males (no groups) and they stayed on the same ward (o.k. different washing and sleeping rooms  ). As far as I can see the gender difference can not be attributed to study design.Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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d_labes ★★★ Berlin, Germany, 2011-03-14 09:32 (5174 d 07:43 ago) @ Dr_Dan Posting: # 6755 Views: 9,015 |
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Dear Dan, dear ElMaestro, dear Helmut, that story reminds me on the old days of IBE. See here on the FDA site for other BE studies which are claimed to have gender specific BE outcomes, i.e. a notable subject-by-formulation interaction (gender-by-formulation interaction). — Regards, Detlew |
Ing. Helmut Schütz