Bioequivalence and Bioavailability Forum

Dear HS!

I have a question regarding estimating the extent of accumulation following repeated study drug administration. I have data from a single dose PK study and I would like to estimate the extent of accumulation in AUCs in the case of repeated study drug administrations.

According to Cawello (2003, page 61-62) "The extent of accumulation can be calculated by the ratio of the dosing interval to the half-life". Accumulation index R = 1/(1-2^-ε) where ε = dosing interval divided by half-life.

I suppose the accumulation is based on two assumptions

• Accumulation refers to accumulation in steady state conditions. Cawello (2003, page 58) "After about 5 half-lives, the equilibrium is practically achieved"
  
• The formula for estimating the extent of accumulation is based on the assumption of a one-compartmental model following an IV bolus.

I have to questions in this context:

1. In the case that the decline over time can be described by a biexponential decline (two-compartmental model) following an IV bolus with an initial and terminal phase which half-life should be used to estimate the extent of accumulation? I think the terminal half-life is not suitable as the theory of accumulation was developed on assumption of a one-compartmental model. right? I think the effective or non-compartmental half-life calculated as log(2) × MRT would be more suitable. Do you agree?
   
2. In the case of only 2 to 4 repeated administration, steady state may not be reached according to Cawello (2003, page 58). In this case I would estimate the accumulation in AUCs based on the principle of superposition. Do you agree?

Best regards

Martin