Dr.Pravin
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Ahmedabad,
2006-10-30 07:23
(6359 d 15:49 ago)

Posting: # 332
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 Steady state study of long half life drug for BA/BE [Design Issues]

Good Morning Dear,

I want to know about the specific guidline which give me the details about the steady state study for long half life drugs (with active metabolites).

I face problem with design issue and protocol preparation.

reply me soon

Regards
Dr Pravin Ahir

Dr.Pravin Ahir
Co-Investigator,
Accutest Research Pvt.Lab.(I), Ltd.
Ahmedabad
Helmut
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Vienna, Austria,
2006-10-30 15:22
(6359 d 07:49 ago)

@ Dr.Pravin
Posting: # 342
Views: 9,601
 

 Steady state study of long half life drug for BA/BE

Dear Pravin!

❝ I want to know about the specific guidline which give me the details about the steady state study for long half life drugs(with active metabolites).


I don't know of any specific guidelines, but may give you some hints:
In order to reach steady state conditions, you should apply the accumulation index for the compound (often a metabolite) with the longest half life first (although strictly speaking only valid for a one-compartment model, it may serve as a first approximation):
            1
  R = ──────────────
      1 - e -kel × τ

whereas
  R   Accumulation index (concentrations in steady state compared to single dose)
  kel Elimination rate constant
  τ   Dosage interval

For example if your drug has an elimination half life of 16 hours and you are dosing once a day, R = 1.55; if your drug's half life is 30 hours, R = 2.45.
First you should play around with this formula, in order to figure out whether
  • there are any problems related to safety expected with the higher concentrations (ethical reasons: it may be impossible to perform the study in healthy volunteers), and
  • is the analytical method still within its boundaries (may need revalidation).
One example of a drug where a steady state study in healthy subjects is infeasible due to ethical reasons is the tricylcic antidepressant amitriptyline with a reported half life of 9-36 hours, and the major active metabolite nortriptyline (half life 18-60 hours): Rparent = 1.19-2.70, Rmetabolite = 1.66-4.13.

You should also consider any known genetic polymorphism of the drug; in such a case you should only include panels of subjects of known phenotype or genotype for the polymorphism in question (i.e., 'fast' or 'extensive' metabolizers).

As a general rule you may expect steady state conditions after at least 3 half lives, but I would recommend at least 5 half lives.
Unfortunatelly your problem is a quite nasty one, so this post may only serve as an entry point... ;-)
At least you don't have to bother about a wash-out period, because you directly switch from one formulation to the other.

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Dr.Pravin
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Ahmedabad,
2006-10-31 06:15
(6358 d 16:56 ago)

@ Helmut
Posting: # 345
Views: 5,862
 

 Steady state study of long half life drug for BA/BE

Ya You are true but,
drug like Fluoxetine and its active metabolite Norfluoxetine half life is 90 hrs so in such cases what we do.

Dr.Pravin Ahir
Co-Investigator,
Accutest Research Pvt.Lab.(I), Ltd.
Ahmedabad
Helmut
★★★
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Homepage
Vienna, Austria,
2006-10-31 13:28
(6358 d 09:43 ago)

@ Dr.Pravin
Posting: # 348
Views: 6,285
 

 Steady state study of long half life drug for BA/BE

Dear Pravin!

❝ [...] drug like Fluoxetine and its active metabolite Norfluoxetine half life is 90 hrs so in such cases what we do.


OK, this is really a quite nasty compund. :-(
Just as an example have a look at this paper:

Pan RN, Chen TH, Huang CSH, and CH Hsiong
Pharmacokinetics and Bioequivalent Study of Generic Fluoxetine Capsules Preparation
Journal of Food and Drug Analysis 10(1), 13–7 (2002)

20mg were administered to 8 subjects b.i.d. for 13 days. According to the reported half life for the reference of 87.2±37.2 hours one might calculate an accumulation factor of 11.0±15.5, which is not reflected in the data (Figure 5); I would estimate the accumulation in the study as about 4 (200ng/mL instead of 50ng/mL).
Since for normal distributed data P(mu+sigma) = 0.15866, one may assume that at least one subject (0.15866×8) showed a half life of >87.2+37.2 or more than 124.4 hours, therefore steady state conditions were not obtained in all subjects…

BTW, Martindale (2002) reports a half life of 4-16 days for norfluoexetine, which also makes steady-state conditions in healthy subjects infeasible.
At least you may opt for a parallel design, OAD dosing.

Quoting

A Marzo
Bioequivalence Behind the Scenes
Pharmaceutical Development and Regulation 1(3), 179–89 (2003)

“A long elimination half-life […] calls for decision making about study design, namely crossover or parallel group design, the latter design being more adequate for drugs cleared with a half-life >10 days. Ethical problems concerning drug administration in healthy individuals (e.g. […] in a repeated-dose regimen) is another issue. Drugs that produce unacceptable side effects in a repeated-dose regimen should be studied in healthy volunteers only in single dose.”

In such a case IMHO it is imperative to go for a ‘Scientific Advisory Meeting’ with the regulators in the planning phase of the study.

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