Timed-release formulation to avoid drug-drug interaction between diltiazem and midazolam

The purpose of this study was to investigate whether the use of a timed-release (TR) drug formulation can avoid unfavorable pharmacokinetic drug-drug interactions in vivo. First, the effects of the time interval between administration of midazolam and diltiazem on the known drug-drug interaction between these drugs were investigated in dogs. When dogs were given midazolam orally at the same time they were orally given an aqueous diltiazem solution, the area under the plasma concentration-time curves of midazolam increased significantly compared with that of midazolam given orally in the absence of diltiazem. However, there was no significant difference in pharmacokinetics of midazolam when the diltiazem solution was administered 1-2 h after midazolam. Tests on a TR formulation containing diltiazem demonstrated that the first appearance of diltiazem in plasma occurs at 2.6 +/- 0.5 h in dogs. Subsequent tests showed that the plasma concentration-time profile of midazolam after concurrent oral administration of the diltiazem TR formulation was almost the same as that of midazolam administered alone. These results demonstrate that a TR formulation of diltiazem can avoid the interaction between diltiazem and midazolam by creating a time interval between absorption of drugs in vivo, without the need for closely controlling the time of drug administration.