COADMINISTRATION OF NEFAZODONE AND BENZODIAZEPINES .2. A PHARMACOKINETIC INTERACTION STUDY WITH TRIAZOLAM

This study was conducted to determine the potential for an interaction between nefazodone, a new antidepressant, and triazolam after a singl e dose of triazolam and multiple doses of nefazodone in a randomized, double-blind, placebo-controlled study in healthy male volunteers. The metabolism of triazolam is dependent on cytochrome P450 3A4, and beca use nefazodone has been shown in vitro to be an inhibitor of this isoe nzyme, this study was conducted to assess the potential for an interac tion between the two drugs. Twelve subjects were assigned to one of tw o groups and received an oral dose of either placebo or 0.25 mg of tri azolam on days 1 and 2. Nefazodone (200 mg) was administered twice dai ly from the evening of day 2 to the morning of day 9. Subjects receive d either 0.25 mg of triazolam or placebo with the nefazodone dose on t he mornings of days 8 and 9. Serial blood samples were collected on th e mornings of days 1, 2, 8, and 9 for the analysis of triazolam by a v alidated gas chromatography/electron capture detection method and on d ays 8 and 9 for the analysis of nefazodone and its metabolites, hydrox ynefazodone (HO-nefazodone) and m-chlorophenylpiperazine (mCPP), by a validated highperformance liquid chromatography/ultraviolet method. No ncompartmental pharmacokinetic analysis showed that there was no effec t of triazolam on the pharmacokinetics of nefazodone, HO-nefazodone, o r mCPP after the coadministration of triazolam and nefazodone, There w as a significant effect of 200 mg of nefazodone twice daily on the pha rmacokinetics of triazolam. Mean triazolam peak concentration values i ncreased (p = 0.003) from 2.33 to 3.88 ng/ml when triazolam was admini stered alone and in combination with nefazodone, respectively, Corresp onding mean triazolam area under the curve values increased (p < 0.001 ) from 8.14 to 31.74 ng . h/ml. The plasma protein binding of triazola m was approximately 85% when triazolam was given alone and when given concurrently with nefazodone. The increase in triazolam concentrations in plasma appears to be attributable to the inhibition of cytochrome P450 3A4 metabolism by nefazodone. If triazolam is coadministered with nefazodone, a reduction in the triazolam dosage is recommended; no do sage adjustment is required for nefazodone.