COMPARISON OF THE STEADY-STATE PHARMACOKINETICS OF NEFAZODONE AFTER ADMINISTRATION OF 200 MG TWICE-DAILY OR 400 MG ONCE-DAILY IN THE MORNING OR EVENING

1 The steady-state pharmacokinetics of nefazodone, an antidepressant d rug with non-linear pharmacokinetics, were determined in a multiple-do se, three-period crossover study in 24 male volunteers to evaluate whe ther administration of the same total daily dose of nefazodone by diff erent dosing schedules has an effect on systemic exposure to the drug and its metabolites. 2 Three treatments administered were: a 400 mg do se once daily in the a.m. (treatment 1) or in the p.m. (treatment 2) f or 5 days or a 200 mg twice daily (every 12 h, a.m. and p.m.) dose dai ly for 7 days (treatment 3). Prior to the administration of the 400 mg once daily dose, the subjects were administered 200 mg nefazodone onc e daily (a.m. or p.m.) for 2 days. There was a 7 day washout between t reatments. 3 Serial blood samples were collected up to 72 h post dose for treatment 1 and treatment 2 and up to 84 h post a.m. dose for trea tment 3 on day 7 for determination of pharmacokinetic parameters. Bloo d samples for trough (C-min) plasma concentrations were also obtained on days 5, 6 and 7 of each treatment to assess attainment of steady st ate. Plasma samples were assayed for nefazodone and its metabolites, h ydroxynefazodone, m-chlorophenylpiperazine and triazoledione by a vali dated h.p.l.c./u.v. assay. 4 The C-min data indicated that nefazodone and its metabolites reached steady state by study day 5 of each treatm ent period. 5 Mean steady-state pharmacokinetic parameter values were similar among treatments. Statistical analyses indicated that, as refl ected by AUC(0,24 h) and the ratios of individual nefazodone metabolit e AUCs to nefazodone AUC over a dosing interval, there were no differe nces in steady-state exposure to nefazodone and its metabolites among treatments. For NEF, AUC(0,24h) (point estimate and 90% CI) values wer e 102% (86%,119%) for 400 mg a.m. and 91% (76%,105%) for 400 mg p.m. w hen compared with the 200 mg twice daily. 6 Although there were some s mall differences in mean pharmacokinetic parameter values after a.m. a nd p.m. administration, no consistent diurnal variation was observed i n the pharmacokinetics of nefazodone or its metabolites. 7 There were no serious or unexpected adverse events noted in the study. 8 It is co ncluded that despite the nonlinearity in the pharmacokinetics of nefaz odone, the exposure to nefazodone and its metabolites is comparable fo r the once daily (400 mg) and twice daily (200 mg) treatments.