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 a ntidepressant 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 mo rning 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 m orning dose on days 7, 14, 16, 15 and 21 for pharmacokinetic analysis of plasma levels of nefazodone (NEF) and its metabolites, hydroxynefaz odone (HO-NEF), m-chlorophenylpiperazine (mCPP) and triazoledione (DIO NE), which were determined by validated HPLC/UV assay methods. The C-m in, results indicated that when nefazodone was administered at a dose of 100 mg b.i.d., steady-state plasma levels of parent compound and it s 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 t hen decreased back to 100 mg b.i.d., new steady-state plasma levels we re 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 s tatistically significant differences in C-max or AUC values for nefazo done or its metabolites between study days 7, 18 and 21. Also consiste nt with the known nonlinear pharmacokinetics of nefazodone, the mean n efazodone steady-state C-max and AUC values for the 200-mg dose were t hree fold and four fold greater, respectively, than those at the 100-m g dose level. Intrasubject variability (% cv) for NEF and its metaboli tes ranged from 13% to 24% for C-max and AUC after 100 mg b.i.d.. Inte rsubject variability was considerably greater and ran (red from 29% to 131% for C-max and AUC after the same dose.