Bioequivalence and Bioavailability Forum

Dear Martin!

❝ The question of linear PK (dose-proportionality) is also addressed in these kind of studies using data after first study drug administration (usually several doses are studied).

❝

❝ Thanks, wonderful idea to check AUC_inf from previous single dose PK study with AUC_tau obtained from the repeated dose toxicity study (i.e. AUC following last study drug administration)…

Well, that’s not my invention.
The problem of between-study comparisons is unresolved (variability!). I don’t know how reproducible results from your highly standardized nice rodents are, but in humans a serious comparison is always done in the same study (single dose profile > saturation > steady state profile; paired test – assuming no period effects, of course).

❝ AUC_tau=AUC_inf in the case of accumulation.

❝ AUC_tau>AUC_inf indicate nonlinear PK.

Exactly.

❝ Interpretation of study results may get complicated in the case that dose-proportionality holds after first study drug administration but AUC_tau after repeated study drug administration is larger than AUC_inf.

OK, I’m not an expert in pre-clinical PK. But for a new drug in humans IMHO the assessment would depend on the clinical indication. If the drug is intended for long-term use I would definitely concentrate on MD data (single dose only supportive). For an analgetic given only occasionally, I would not bother too much on nonlinear PK in steady state.

❝ Any idea what this result [linear PK in SD, nonlinear PK in steady state] could indicate?

Well, any one of the effects I mentioned in my previous post (time dependent PK, enzyme inhibition, capacity limited excretion, etc.).
Especially with biologics I have seen really weird stuff: Concentrations increased, stayed limited time at some ‘pseudo steady state’, and subsequently decreased to ‘true state state’. In this case the drug behaved as expected only for limited time (the first ‘steady state’) until an enzyme system was induced, which finally led to another (lower) steady state. That’s the tricky thing with predictions of plasma levels from single dose data.

A simple example (modified from Danielsson & Weiner, PK model 22):

Single dose study; 1 h infusion of 40 units (bottom left). It was decided based on a simulation (top ▬) to start the multiple dose study with a 1 h infusion of 120 units as a loading dose, followed by 0.5 h infusions of 40 units (τ = 8 h).
What we see, is auto-induction (increased clearance) which leads to a steady state of only ~50% (▬) of the expected one. Unless we have performed the experiment, we never can be sure!

‘Hard core pharmacokineticists’ even support such a statement:

Unless we have performed steady state studies – at different dose levels –
we do know nothing about the PK of a drug.