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 drug with non-linear pharmacokinetics, were determined in a multiple-dose, three-period crossover study in 24 male volunteers to evaluate whether administration of the same total daily dose of nefazodone by different dosing schedules has an effect on systemic exposure to the drug and its metabolites. 2. Three treatments administered were: a 400 mg dose once daily in the a.m. (treatment 1) or in the p.m. (treatment 2) for 5 days or a 200 mg twice daily (every 12 h, a.m. and p.m.) dose daily for 7 days (treatment 3). Prior to the administration of the 400 mg once daily dose, the subjects were administered 200 mg nefazodone once daily (a.m. or p.m.) for 2 days. There was a 7 day washout between treatments. 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 treatment 3 on day 7 for determination of pharmacokinetic parameters. Blood samples for trough (Cmin) plasma concentrations were also obtained on days 5, 6 and 7 of each treatment to assess attainment of steady state. Plasma samples were assayed for nefazodone and its metabolites, hydroxynefazodone, m-chlorophenylpiperazine and triazoledione by a validated h.p.l.c./u.v. assay. 4. The Cmin data indicated that nefazodone and its metabolites reached steady state by study day 5 of each treatment period. 5. Mean steady-state pharmacokinetic parameter values were similar among treatments. Statistical analyses indicated that, as reflected by AUC(0,24 h) and the ratios of individual nefazodone metabolite AUCs to nefazodone AUC over a dosing interval, there were no differences in steady-state exposure to nefazodone and its metabolites among treatments. For NEF, AUC(0,24 h) (point estimate and 90% CI) values were 102% (86%, 119%) for 400 mg a.m. and 91% (76%, 105%) for 400 mg p.m. when compared with the 200 mg twice daily. 6. Although there were some small differences in mean pharmacokinetic parameter values after a.m. and p.m. administration, no consistent diurnal variation was observed in the pharmacokinetics of nefazodone or its metabolites. 7. There were no serious or unexpected adverse events noted in the study. 8. It is concluded that despite the nonlinearity in the pharmacokinetics of nefazodone, the exposure to nefazodone and its metabolites is comparable for the once daily (400 mg) and twice daily (200 mg) treatments.