Nonlinear pharmacokinetics of nefazodone after escalating single and multiple oral doses.

The single- and multiple-dose pharmacokinetics of nefazodone and its metabolites, hydroxynefazodone, p-hydroxynefazodone, and m-chlorophenylpiperazine were investigated in two groups of 18 healthy male volunteers, employing three-period complete crossover designs. In one group, single 50-mg, 100-mg, and 200-mg oral doses of nefazodone hydrochloride were administered with a 1-week washout between treatments. In the other group, doses of 50 mg, 100 mg, and 200 mg were administered twice a day (every 12 hours) for 7.5 days (15 doses) with a 1-week washout between treatments. Serial plasma samples were obtained in both groups and assayed for nefazodone, hydroxynefazodone, m-chlorophenylpiperazine, and p-hydroxynefazodone. Cmax plasma levels of nefazodone and hydroxynefazodone were attained within 2 hours of administration of nefazodone; tmax for m-chlorophenylpiperazine was more delayed, and p-hydroxynefazodone levels were generally below the assay limit. On repeated twice-daily dosing of nefazodone, steady-state levels of the drug and its metabolites were reached within 3 days. Mean single-dose plasma half-life (t1/2) values for nefazodone increased from approximately 1 hour at a 50-mg dose to approximately 2 hours at a 200-mg dose; at steady state, t1/2 values increased from approximately 2 hours at 50 mg twice daily to approximately 3.7 hours at 200 mg twice daily. Whereas dose increased in the proportion of 1:2:4, mean single-dose AUC0-infinity for nefazodone increased in the proportion of 1:3.3:8.9 and mean steady-state AUC0-tau for nefazodone increased in the proportion of 1:4.2:16.8. Plasma levels of hydroxynefazodone paralleled those of nefazodone and were approximately 33% of nefazodone levels at each dose level. Plasma levels of m-chlorophenylpiperazine were only approximately 10% those of nefazodone. Within the dosage range of 50-200 mg of nefazodone hydrochloride, nefazodone and hydroxynefazodone exhibited nonlinear pharmacokinetics; m-chlorophenylpiperazine, a minor metabolite, appeared to exhibit linear pharmacokinetics.