Ahmed meeran
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2006-09-12 08:10
(6407 d 04:23 ago)

Posting: # 249
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 BE at Steady state [Design Issues]

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
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2006-09-21 15:38
(6397 d 20:55 ago)

@ Ahmed meeran
Posting: # 254
Views: 8,352
 

 BE at Steady state

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.

  1. EJ Van Hoogdalem et al.
    Multiple dose bioequivalence study with josamycin propionate, a drug with highly variable kinetics, in healthy volunteers
    Int J Clin Pharmacol Ther 34/5, 202-207 (1996)
  2. H Blume et al.
    Advantages of a steady-state crossover design in assessment of bioequivalence of highly variable drugs: propafenone
    Eur J Pharmaceut Sci 2, 385-393 (1994)

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Ahmed meeran
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2006-10-03 15:09
(6385 d 21:24 ago)

@ Helmut
Posting: # 269
Views: 7,899
 

 BE at Steady state

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
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2006-10-03 15:55
(6385 d 20:38 ago)

@ Ahmed meeran
Posting: # 270
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 Nonlinear PK (Sweden)

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.

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Ahmed meeran
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2006-10-10 16:02
(6378 d 20:30 ago)

@ Helmut
Posting: # 300
Views: 7,951
 

 Nonlinear PK (Sweden)

Dear Dr. Helmut,

Thanks for your advice.

Ahmed
Ahmed meeran
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2006-10-30 12:27
(6358 d 23:05 ago)

@ Helmut
Posting: # 337
Views: 7,874
 

 Nonlinear PK (Sweden)

Dear Dr. Helmut,

How to design steady state BE for a immediate release drug.

With regards,

D.Ahmed
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2006-10-30 14:40
(6358 d 20:53 ago)

@ Ahmed meeran
Posting: # 341
Views: 8,241
 

 Steady state design (EU)

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.
[…] In steady-state studies wash out of the previous treatment last dose can overlap with the build-up of the second treatment, provided the build-up period is sufficiently long (at least three times the terminal half-life).
[…] In order to study bioavailability under steady-state conditions when differences between morning and evening or nightly dosing are known, (e.g. if it is known that the circadian rhythm is known to have an influence on bioavailability), sampling should be carried out over a full 24 hours cycle.

3.3 Characteristics to be investigated

[…] For studies in steady state AUCτ, Cmax, Cmin and fluctuation should be provided.

APPENDIX I

AUCτ: AUC during a dosage interval (τ) in steady state;
Cmax: maximal plasma concentration;
Cmin: minimal plasma concentration;
Cav: average plasma concentration;
Fluctuation: (Cmax-Cmin)/Cav.

Cav = AUCτ/τ

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.

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