Bioequivalence and Bioavailability Forum

Dear Shabana,

thanks for for your fruitful contribution.

❝ As i understand washout periods are meant to "wash out" the drug from the body, completely remove it, or as nearly completely as possible (correct me here if I am wrong).

Yes, you’re right – in order to apply a cross-over design, we must consider not only PK, but all pharmacological effects (with may appear as a residual effect) as well. Therefore PK is just a part of successful study planning!

❝ Most PK scientists would tell us that the consensus on five half lives for washout period came from the fact that 96.9 % of the drug has been removed from the body by the time five half lives are over. […] By three half-lives, 87.5% of the drug is lost, by four half-lives 93.5% of the drug is removed.

96.9% are cleared after 5 half lives for a 1-compartment open model, or to be precise 1-½ⁱ applies (i is a multiple of the half life):
  i       % of steady state
  3       87.5
  4       93.8
  4.323   95.0
  5       96.9
  5.294   97.5
  5.622   98.0
  6.623   99.0
  7       99.2
  9.966   99.900
 10       99.902
I would not call this a consensus, but rather a convention.
For anything more complicated – and even a 2-compartment model is ‘complicated’ in this respect, total clearance can become a pretty nasty function depending on all rate constants and volumes of distribution involved (not even thinking about drugs with nonlinear PK of the MM-type).

❝ Of course some regulatory bodies give you the option of applying at least three half-lives that emcompasses both washout and run-up. By three half-lives, 87.5% of the drug is lost, by four half-lives 93.5% of the drug is removed. So i guess if you are happy with 87.5% (=three half-lives) of the drug lost from the body, no problems in accommodating with the design they suggest.

Don’t get me wrong. Personally I think three half lives are too short either!
I was only arguing against your initial statement…

❝ no regulatory body recommends a washout less than at least 7-10 half-lives in steady state studies.

… and was referring to some regulatory examples

❝ Whether you call it "washout period" or "build-up", they are meant to remove the drug from the body.

The former, yes; the latter no! “Build-up” is just synonymous to the saturation phase you have to apply in the beginning of each treatment period.

❝ I think the operative word here is "at least"; the regulatory recommends a lower margin, and puts no tabs on the upper margin. Its up to the sponsor to arrive on a judicious upper margin,balancing the effects of subject dropout and unacceptable results.

Full ACK

❝ When you say

❝ ❝ Forget about washouts in steady-state; they are just a waste of time, increasing the chance of subjects dropping out from the study

❝ do you mean you are totally againt washout periods in biostudies involving steady state???

IMHO (at least for drugs with linear PK) they don’t make any sense. Again, for a fixed dosage level given at the same dosage interval we will obtain exactly the same steady state level, irrespectively which level we are starting the “build up” from (=‘zero’ for subjects in period 1, 12.5% residual after 3 half lives, 3.1% residual after 5 half lives, etc). In order to apply the superposition principle (SD AUC_0–∞ = MD AUC_0–τ), we must demonstrate achievement of steady state anyhow (e.g., three pre-dose concentrations with slope≈0).
I will be happy if anyone would come up with a simulation where the profile in steady state is substantially different if an additional wash-out is applied.

❝ I wonder how this statement would go down with Ethics Committees???

Which problems do you expect from IECs?
You have a shorter duration of the study, the number of samples per subject is reduced by one (since the last sample of the profile in period 1 is the first pre-dose sample in the build up).

❝ And you have to agree that the regulatory bodies, in general, recommend a longer washout in steady-state studies as compared to single dose studies.

Yes, but that does not disqualify a switch-over design

❝ ❝ you would get the same plasma concentrations no matter what initial concentration you start with.

❝ I am afraid i don't think this can be treated as a blanket statement, though it may be true in most cases.

Consequently, you have to know the PK of your drug.
But at least for drugs with ‘uncomplicated PK’ the statement holds true.

❝ How will you explain drug toxicity then???

Simple: the concentration is above the toxicity level…
But the discussion started with – and should be confined within – steady state designs for bioequivalence assessment.

❝ what about specifically those drugs that accumulate on steady state dosing?

I don’t see the problem.
Actually my example (t_½ 10 h, τ 24 h) shows an accumulation index $$R=\frac{1}{1-\exp (-k_\textrm{10}\cdot \tau)}$$ of 1.23 (i.e., C_ss,max is 23% higher than C_max).

❝ I believe that is a major function of "therapeutic drug monitoring".

No, that’s a different cup of tea.
In TDM you must have

• either have a clearly accepted therapeutic range
  
• or an individually titrated concentration range.

❝ OK, about DKMA […] I was merely commenting on how people would like to interpret guidelines in a crooked manner.

Yes, but this ‘people’ are belonging to a European Regulatory Body.