COADMINISTRATION OF NEFAZODONE AND BENZODIAZEPINES .3. A PHARMACOKINETIC INTERACTION STUDY WITH ALPRAZOLAM

This study was conducted to determine the potential antidepressant, and alprazolam after single- and multiple-dose administration in a randomized, double-blind, parallel-group, placebo-controlled study in 48 healthy male volunteers. A group of 12 subjects received either placebo twice daily, 1 mg of alprazolam twice daily, 200 mg of nefazodone twice daily, or the combination of 1 mg of alprazolam and 200 mg of nefazodone twice daily for 7 days. Serial blood samples were collected after dosing on day 1 and day 7 and before the morning dose on days 4, 5, and 6 for the determination of alprazolam and its metabolites alpha-hydroxyalprazolam (AOH) and 4-hydroxyalprazolam (4OH) and nefazodone and its metabolites hydroxynefazodone (HO-nefazodone), m-chlorophenylpiperazine (mCPP), and a triazole dione metabolite (dione) by validated high-performance liquid chromatography methods. Steady-state levels in plasma mere reached by day 4 for alprazolam, 4OH, nefazodone, HO-nefazodone, mCPP, and dione. Noncompartmental pharmacokinetic analysis showed that at steady state, alprazolam C-max and AUC(tau) values significantly increased approximately twofold and 4OH C-max and AUC(tau) values significantly decreased by 40 and 26%, respectively, when nefazodone was coadministered with alprazolam. There was no effect of alprazolam on the single-dose or steady-state pharmacokinetics of nefazodone, HO-nefazodone, or done after the coadministration of alprazolam and nefazodone. However, the mean steady-state mCPP C-max and AUC(tau) significantly increased by approximately threefold and t(1/2) values significantly increased by approximately twofold after the coadministration of alprazolam and nefazodone in comparison to those when nefazodone was given alone. Competitive inhibition between alprazolam and nefazodone metabolism at cytochrome P450 3A4 may be responsible for the pharmacokinetic interaction when alprazolam and nefazodone were coadministered. No adjustment of nefazodone dosage is required when nefazodone and alprazolam are coadministered. Because alprazolam concentrations in plasma are increased in the presence of nefazodone, a reduction in alprazolam dosage is recommended when the two agents are coadministered.