Bioequivalence and Bioavailability Forum

❝ [...] do we need to take blood samples till 5 half life of the drug and

❝ pre-dose sample also require to be taken prior to 4th day dosing? If we

❝ following parameters to be considered for BE Parameters to be calculated:

❝ Cmax

❝ AUCtau

❝ Tmax

❝ Kel

❝ and t1/2

• You have to analyze the first pre-dose sample (day 1) in order to demonstrate lack of interferences in 'real-world' (not spiked) samples.
  
• You have to demonstrate that you reached steady state on day 4 - therefore some pre-dose samples prior to day 4 have to be analyzed (see this post or that one).
  
• Only if your drug shows no diurnal variability, the first 8 h profile on day 4 is sufficient. If your drug's PK is influenced by some circadian rhythms, you have to measure a full 24 hours cycle (i.e., three profiles). Nasty, because the number of samples might be limited and you still have to 'catch' C_max. This might challenge the bioanalytical method, because the individual sample volumes have to be reduced in order to stay within the total volume of a blood donation.
  
• There is no need to sample beyond the profile's last time point. You can't get an unbiased estimate of k_el in steady state by NCA-methods. Don't get confused by papers of the innovator: In an NDA studying elimination from steady state does make sense – if PK modeling is aimed at. In BE nobody is interested in this metric (except in Taiwan and China – see this thread).
  
• Don't use a washout – switch on day 5 directly to the other formulation (see this post).

❝ Bioequivalence to be concluded if the Cmax and AUCtau are within 80-125%.