Steady state pharmacokinetics of nefazodone in subjects with normal and impaired renal function

The steady-state pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were compared in subjects with normal and impaired renal function. Patients: The Study was of parallel group design which included 7 subjects with normal (NOR) renal function, CL(CR) greater than or equal to 72 ml . min(-1) . 1.73 m(-2), 6 with moderate (MOD) renal impairment, CL(CR) 31-60 ml . min(-1). 1.73 m(-2) and 9 with severe (SEV) renal impairment, CL(CR) less than or equal to 30 ml . min(-1). 1.73 m(-2). Subjects in each renal function group received a 100-mg oral dose of nefazodone hydrochloride BID for 7 days and a single morning dose on day 8. Starting 48 h after the last 100-mg dose, 200-mg doses were administered on a similar schedule to 3, 4 and 3 subjects from each renal function group (NOR, MOD and SEV, respectively). Single trough blood samples just prior to each morning dose (C-min) and serial samples after the dose on day 8 were obtained at each dose level for pharmacokinetic analysis. Plasma samples were assayed by a specific HPLC method for NEF, HO-NEF and mCPP. The CMIN data indicated that steady state was attained by the third day of BID administration of both the 100- and 200-mg doses of nefazodone, regardless of degree of renal function. Both NEF and HO-NEF attained steady-state C-max within 2 h after administration of nefazodone; t(max) for mCPP was less defined and more delayed. HO-NEF and mCPP plasma levels were about 1/3 and < 1/10 those of NEF, respectively, regardless of the status of renal function. Steady-state systemic exposure of NEF and HO-NEE as reflected by AUC and C-max, and elimination t(1/2) values did not differ significantly among renal function groups. Conclusion: The study results suggest that dose adjustments may not be necessary, but nefazodone should be used with caution in the presence of severe renal impairment.