Nefazodone pharmacokinetics: assessment of nonlinearity,intra-subject variability and time to attain steady-state plasma concentrations after dose escalation and de-escalation

Objective: The time required to reach steady-state plasma levels after an increase and a subsequent decrease in the dose of nefazodone, an antidepressant drug with nonlinear pharmacokinetics, was assessed in 24 healthy, male volunteers. Methods: Each subject was administered 100 mg nefazodone hydrochloride b.i.d. (q 12 h) from study day 1 to 7, 200 mg b.i.d. from study day 8 to 14 and 100 mg b.i.d. from study day 15 to 21. Trough (C_min blood samples were obtained just prior to the morning dose on days 4–7, 11–14 and 16–21 to evaluate the attainment of steady state. Serial blood samples were collected for 12 h after the morning dose on days 7, 14, 16, 18 and 21 for pharmacokinetic analysis of plasma levels of nefazodone (NEF) and its metabolites, hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and triazoledione (DIONE), which were determined by validated HPLC/UV assay methods. The C_min results indicated that when nefazodone was administered at a dose of 100 mg b.i.d., steady-state plasma levels of parent compound and its metabolites were attained by the 4th day (i.e., after six doses) and when the dose was increased from 100 mg b.i.d. to 200 mg b.i.d. and then decreased back to 100 mg b.i.d., new steady-state plasma levels were also reached by the beginning of the 3rd or 4th day of each regimen. Consistent with the attainment of steady-state data, there were no statistically significant differences in C_max or AUC values for nefazodone or its metabolites between study days 7, 18 and 21. Also consistent with the known nonlinear pharmacokinetics of nefazodone, the mean nefazodone steady-state C_max and AUC values for the 200-mg dose were three fold and four fold greater, respectively, than those at the 100-mg dose level. Intrasubject variability (% cv) for NEF and its metabolites ranged from 13% to 24% for C_max and AUC after 100 mg b.i.d.. Intersubject variability was considerably greater and ranged from 29% to 131% for C_max and AUC after the same dose. Received: 12 June 1995/Accepted in revised form: 2 October 1995