Ahmed meeran ● 2006-09-12 08:10 (6815 d 16:12 ago) Posting: # 249 Views: 11,016 |
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Dear Dr. Helmut All the regulatory guidlines talks about conducting Bioequivalence study in single dose and at steady state conditions. For which type of drugs conducting a Bioequivalence study at steady state conditions is necessary. For performing Bioequivalence study at steady state whether the sample size calculation is same as that of single dose study. If Bioequivalence study is performed at steady state whether it will meet the acceptance criteria with small no of subjects than a single dose study. Please guide me in these issues Ahmed |
Helmut ★★★ ![]() ![]() Vienna, Austria, 2006-09-21 15:38 (6806 d 08:45 ago) @ Ahmed meeran Posting: # 254 Views: 9,660 |
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Dear Ahmed! ❝ All the regulatory guidlines talks about conducting Bioequivalence study ❝ in single dose and at steady state conditions. Not all of the guidelines! Generally single dose studies are more sensitive in detecting differences between formulations, especially for rate parameters. ❝ For which type of drugs conducting a Bioequivalence study at steady ❝ state conditions is necessary. Regulatory requirements for steady state studies depend on the type of formulation (modified relase), not on the drug. Steady state studies are generally not needed for immediate release formulations (except for drugs with nonlinear PK and low solubility). ❝ For performing Bioequivalence study at steady state whether the sample ❝ size calculation is same as that of single dose study. In the vast majority of cases variability in steady state is lower than after a single dose (I know of only one rare example where variability was not reduced [1] ). Therefore your single dose sample size in steady state should give you at least equal power. If you want to be sure, you may opt for a pilot study (for a reasonable size see this post and followings).❝ If Bioequivalence study is performed at steady state whether it will meet ❝ the acceptance criteria with small no of subjects than a single dose ❝ study. Most likely (see above), but at least in the European Union steady state studies are no more accepted as a proper mean for a reduction in sample sizes of highly variable drugs (as proposed by Blume et al. [2] ). See also this post on HVDs.
— 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 |
Ahmed meeran ● 2006-10-03 15:09 (6794 d 09:13 ago) @ Helmut Posting: # 269 Views: 9,207 |
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Dear Dr. Helmut, Thanks for your clarification on the issues of steady state BE. When one of my colleague submitted dossier for fluoxetine 20 mg capusule in Sweden it has been queried by Swedish authorities why we had submitted a single dose study on fluoxetine for estabilishing BE. Reason for this is (given by swedish authorities) both fluoxetine and its metabolite nor fluoxetine follows nonlinear kinetics. As per their view, "for substances with nonlinear kinetics normally BE should be estabilshed during the most saturated condtion achieved therapeutically" (Whether it means Steady State conditions ??!!) Kindly help me in providing a proper justification. |
Helmut ★★★ ![]() ![]() Vienna, Austria, 2006-10-03 15:55 (6794 d 08:27 ago) @ Ahmed meeran Posting: # 270 Views: 9,508 |
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Dear Ahmed! ❝ [...] When one of my colleague submitted dossier for fluoxetine 20 mg capusule in sweden it has been queried by swedish authorities why we had submitted a single dose study on fluoxetine for estabilishing BE. Reason for this is (given by swedish authorities) both fluoxetine and its metabolite nor fluoxetine follows nonlinear kinetics. As per their view, "for substances with nonlinear kinetics normally BE should be estabilshed during the most saturated condtion achieved therapeutically" OK, the Swedish statement possibly is a misinterpretation (Dose proportionality of several strengths) of the EU Guidance on BA/BE (#5.4, page 15). For a clarification have a look at the recent Q&A-Document (#9, page 4). ❝ (Whether it means Steady State conditions ??!!) IMHO, no; but in the worst case they want BE demonstrated at the highest recommended dose (according to the SmPC of the reference product), which for fluoxetine means 60 mg (in some countries and for some indications even 80 mg). In such a case a study in healthy volunteers is infeasible (AEs!). Your colleague should consider applying for a Scientic Advice at the Swedish MPA to clarify the question. — 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 |
Ahmed meeran ● 2006-10-10 16:02 (6787 d 08:20 ago) @ Helmut Posting: # 300 Views: 9,269 |
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Dear Dr. Helmut, Thanks for your advice. Ahmed |
Ahmed meeran ● 2006-10-30 12:27 (6767 d 10:55 ago) @ Helmut Posting: # 337 Views: 9,194 |
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Dear Dr. Helmut, How to design steady state BE for a immediate release drug. With regards, D.Ahmed |
Helmut ★★★ ![]() ![]() Vienna, Austria, 2006-10-30 14:40 (6767 d 08:43 ago) @ Ahmed meeran Posting: # 341 Views: 9,613 |
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Dear Ahmed, have a look at the European Guidance on BA/BE: 3.1 Design […] In such steady-state studies the administration scheme should follow the usual dosage recommendations. […] For studies in steady state AUCτ, Cmax, Cmin and fluctuation should be provided. APPENDIX IAUCτ: AUC during a dosage interval (τ) in steady state; Remarks: For the design you should always apply a ‘worst-case-scenario’ for the half life, i.e., never use a mean value from the literature, but the longest reported half life (otherwise the superposition principle of pharmacokinetics [AUC∞ from single dose = AUCτ in steady state] is not valid). Always take pre-dose samples during the saturation phase in order to check compliance. — 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 |