Bioequivalence and Bioavailability Forum

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): R_parent = 1.19-2.70, R_metabolite = 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.