Guidelines for selecting multiple-dose/multiple-dose design trials

Multiple-Dose/Multiple-Dose Design Conditions
1. Specific safety issues are possible that depend on achieving steady-state exposure of both compounds.
2. The interaction is not strictly competitive, e.g., mechanism-based or suicidal inhibition occurs or may occur.
3. A claim that widens the absolute bioequivalency criteria is desired.
4. The time course of induction or inhibition needs to be determined.
5. First dose effects require titration to a standard steady-state dose for either compound.
6. One drug shows a significant accumulation ratio and a single-dose regimen that achieves comparable steady-state concentrations is not feasible.
7. One of the drugs at steady-state concentrations forms a metabolite that produces additive induction or inhibition, which cannot be demonstrated through the administration of larger single doses.
8. Dose-dependent or time-dependent pharmacokinetics, e.g., phenytoin or omeprazole, respectively, leading to at least a 50 to 100% accumulation of parent.