COADMINISTRATION OF NEFAZODONE AND BENZODIAZEPINES .4. A PHARMACOKINETIC INTERACTION STUDY WITH LORAZEPAM

This study was conducted to determine the potential for an interaction between nefazodone (NEF), a new antidepressant, and lorazepam (LOR) a fter single- and multiple-dose administration in a randomized, double- blind, parallel-group, placebo-controlled study in healthy male volunt eers. A total of 12 subjects per group received either placebo (PLA) t wice daily, 2 mg of LOR twice daily, 200 mg of NEF twice daily, or the combination of 2 mg of LOR and 200 mg of NEF (LOR+NEF) twice daily fo r 7 days. Plasma samples were collected after dosing on day 1 and day 7 and before the morning dose on days 4, 5, and 6 for the determinatio n of LOR, NEF, and NEF metabolites hydroxy (HO)-NEF, m-chlorophenylpip erazine (mCPP), and dione by validated high-performance liquid chromat ography methods. Steady-state levels in plasma were reached by day 4 f or LOR, NEF, HO-NEF, mCPP, and dione. Noncompartmental pharmacokinetic analysis showed that there was no effect of LOR on the single dose or steady-state pharmacokinetics of NEF, HO-NEF, or dione after coadmini stration. The steady-state mCPP C-max values decreased 36% for the LOR +NEF group in comparison to that when NEF was given alone. There was n o effect of NEF on the pharmacokinetics of LOR after coadministration. The absence of an interaction appears to be attributable to LOR's met abolic clearance being dependant on conjugation rather than hydroxylat ion. Overall, no change in LOR or NEF dosage is necessary when the two drugs are coadministered.