Bioequivalence and Bioavailability Forum

Hi Sandy,

doesn’t makes sense if you have an accumulation factor ≥1.05 – otherwise you would exclude many subjects, right?

What you could do (only in the first period if you use a switch-over design) is to estimate C_max after the first dose. Example for a one-compartment model: A 187.08, k_a 1, k_el 0.05776 (~t_1/2 12), τ 24, four doses. The time course of C_min is given by A·(1–ℯ^–k_el·t)/(n_D–1). Note that k_a is irrelevant – as long as we don’t approach flip-flop PK. We get:
  t    C
  0   BLQ
 24  46.77 ← C_τ,min
 48  58.46
 72  61.39
 96  62.12 ← C_ss,min
The accumulation factor R_A¹ can be estimated as the ratio of C_ss,min/C_τ,min or 62.12/46.77 = 1.328. This method is model-independent² and applicable to any route of administration. Basic PK tells us that the time course of C_max-values is ~ parallel to the C_min-values. If C_ss,max in the steady state profile was e.g. 200, C_max in SD is estimated as 200/1.328 ~  150 (the value of the model is 148). So the 5% limit for the pre-dose concentration in period 1 would be 7.5 (not 10 – if naïvely applying 5% of C_ss,max).

---

1. AGAH working group pharmacokinetics
   Collection of terms, symbols, equations, and explanations of common pharmacokinetic and pharmacodynamic parameters and some statistical functions
   Association for Applied Human Pharmacology, 16 Feb 2004
   online resource
   
2. Hey, NCA! Regulators will be happy.