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Helmut ★★★   Vienna, Austria, 2006-05-26 16:46 (6918 d 18:35 ago) Posting: # 138 Views: 8,780 |
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Dear all, at IBC's '5th annual Conference on Dissolution Testing, Bioavailability & Bioequivalence' which took place 22-24 May 2006 in Budapest/Hungary we had a little discussion about the generally applied method of average bioequivalence (ABE) in generic substitution. Although conceptually ABE is designed to allow patients to enter a therapy on a generic drug ('Prescribability'), some European countries allow switching from one preparation to another one during therapy ('Switchability'). Formally ABE is not a correct method to assess switchability - which can be assessed by 'Individual BE' (IBE). Interesting in this context is the statement of the Danish Authority (DKMA): 'The Danish Medicines Agency considers that the 90% confidence interval for the ratio test versus reference should include 100% irrespective of whether acceptance limits of 80-125% or narrower are employed. Deviations may be accepted if they can be adequately justified not to have impact on either the overall therapeutic effect or safety profile of the product.' The inclusion of 100% may be difficult to meet if a drug exhibits low variability (i.e., CV <10%), or the sample size is rather high ('to be on the safe side...'. I had to deal with about one deficiency letter / month during the last half year (from Belgium and Germany). Recommendation: don't overpower your study! Another point stated (Table 1) is the narrower acceptance range (AUC, Cmax: 90%-111%) for a couple of drugs / drug classes, namely Aminophylline/Theophylline, Lithium, Thyroxine, Warfarin, Antiepileptics apart from benzodiazepines (Lamotrigine: 90%-110%), Immunosuppressives, Antiarrhythmics, Centrally acting anorectics, and Tricyclic antidepressants. — 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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Dr Andrew Leary ★ Ireland, 2010-08-26 18:56 (5365 d 16:25 ago) @ Helmut Posting: # 5844 Views: 5,640 |
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Hello Helmut et al ❝ Another point stated (Table 1) is the narrower acceptance range (AUC, Cmax: 90%-111%) for a couple of drugs / drug classes, namely Aminophylline/Theophylline, Lithium, Thyroxine, Warfarin, Antiepileptics apart from benzodiazepines (Lamotrigine: 90%-110%), Immunosuppressives, Antiarrhythmics, Centrally acting anorectics, and Tricyclic antidepressants. Further to this, I wonder whether you have any specific tips for BE studies with narrow therapeutic index drugs. I've just been playing with NQuery Advisor which tells me that, as we all know very well, for an intra-subject CV of 23.5% I need a minimum of 24 subjects where acceptance limits are 80% to 125%. If, however, I narrow the limits to 90% to 111.1%, I find that for the same CV I'll need 230 subjects. I had not expected this! I accept that most NTI drugs probably have fairly low intra-subject CVs, but I'm trying to design a study for Levothyroxine where the problem of endogenous levels coupled with the fact that the 600mcg dose does not increase blood levels all that much over baseline means that, in my limited experience anyway, the CVs for AUC can be quite high. [Well over 23.5%.] Any pearls of wisdom to cast before this swine? Best regards Andrew |
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Helmut ★★★ Vienna, Austria, 2010-08-26 19:48 (5365 d 15:33 ago) @ Dr Andrew Leary Posting: # 5845 Views: 5,706 |
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Dear Andrew! ❝ […] I wonder whether you have any specific tips for BE studies with narrow therapeutic index drugs. I've just been playing with NQuery Advisor which tells me that, as we all know very well, for an intra-subject CV of 23.5% I need a minimum of 24 subjects where acceptance limits are 80% to 125%. If, however, I narrow the limits to 90% to 111.1%, I find that for the same CV I'll need 230 subjects. I had not expected this! My dear, science is a cruel mistress. (Paul Shenar as Dr. Laurence) Power curves are unforgiving - especially when you change the T/R-ratio or the acceptance range. ❝ I accept that most NTI drugs probably have fairly low intra-subject CVs, but I'm trying to design a study for Levothyroxine where the problem of endogenous levels coupled with the fact that the 600mcg dose does not increase blood levels all that much over baseline means that, in my limited experience anyway, the CVs for AUC can be quite high. [Well over 23.5%.] Levothyroxine is not considered an NTID in Canada. No product specific GL in the US, but Liothyronine is also not considered an NTID. In Europe NTIDs are assessed on a case-by-case basis. Little is published yet (tacrolimus: AUC 90%-111%, Cmax 80%-125%; ciclosporine: AUC and Cmax 90%-111%). Would be interesting to know how Denmark will defend their requirements (updated on 8 Feb 2010) in the light of European harmonization (all immunosuppressives AUC and Cmax 90%-111% vs. EMA-Q&A tacrolimus AUC 90%-111%, Cmax 80%-125%). — 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 |
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Dr Andrew Leary ★ Ireland, 2010-08-29 11:15 (5363 d 00:06 ago) @ Helmut Posting: # 5864 Views: 5,575 |
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Hello Helmut ❝ Levothyroxine is not considered an NTID in Canada. No product specific GL in the US, but Liothyronine is also not considered an NTID. In fact, there is a US guideline (Levothyroxine), but it is very controversial, with a number of critical papers written about same in the last 10 years. ❝ In Europe NTIDs are assessed on a case-by-case basis. Little is published yet (tacrolimus: AUC 90%-111%, Cmax 80%-125%; ciclosporine: AUC and Cmax 90%-111%). ❝ Would be interesting to know how Denmark will defend their requirements (updated on 8 Feb 2010) in the light of European harmonization (all immunosuppressives AUC and Cmax 90%-111% vs. EMA-Q&A tacrolimus AUC 90%-111%, Cmax 80%-125%). Fair comment. I'll tell my client to seek regulatory advice before proceeding. Kind regards Andrew |
Ing. Helmut Schütz