Steady-state pharmacokinetics of nefazodone in subjects with normal and impaired renal function |
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Authors: | R H Barbhaiya M E Brady U A Shukla D S Greene |
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Institution: | (1) Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, 08543-4000 Princeton, NJ, USA;(2) Present address: Hoechst-Roussel Pharmaceuticals Inc., 08876-1258 Somerville, NJ, USA |
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Abstract: | 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, CLCR 72 ml·min–1·1.73 m–2, 6 with moderate (MOD) renal impairment, CLCR 31–60 ml·min–1·1.73 m–2 and 9 with severe (SEV) renal impairment, CLCR 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 (Cmin) 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 Cmax within 2 h after administration of nefazodone; tmax 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-NEF, as reflected by AUC and Cmax, and elimination t1/2 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. |
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Keywords: | Nefazodone Renal impairment pharmacokinetics antidepressive agents |
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