Study Design Considerations

Dosing Regimens. One of the major considerations in designing a drug-drug interaction study is whether to dose the substrate (S) or the interacting drug (I) as single dose or chronically (multiple dose).

The selection of the dosing regimens will depend on a. Whether the S or I is dosed acutely or chronically in the clinical setting b. Safety considerations including whether the drugs are considered narrow therapeutic index or not c. The pharmacokinetic and pharmacodynamic characteristics of the S and I

d. The need to assess induction or inhibition.

A recent survey of all approved new molecular entities, approved between 1992-1997, showed that the preferred dosing regimen was to dose both I and S to steady state (47% of all studies) while in 30% of the cases one of the drugs was dosed to steady state [96]. The use of such designs is a reflection of the clinical use of these drugs and the fact that for inducers and some inihibtors it might take several days to see the full extent of the interaction. As an illustration to this point, an interaction study between alfentanyl and erythromycin did not show any interaction on the clearance of alfentanyl. However, after a seven-day course of 500 mg erythromycin twice daily, there was a 25% decrease in alfentanyl clearance and a 60% increase in the alfentanyl half-life [97]. Another complicating factor in the ability to extrapolate the single dose findings to steady-state situations is the potential for certain inhibitors to also act as inducers when given on a long-term basis. One such drug is the protease inhibitor ritonavir.

On the other hand, the vast majority of absorption-based drug interaction studies with drugs such as antacids or drugs that affect gastric motility use a single single-dose study design since with this design one can determine whether the bioavailability of the S is affected.

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