Influence of hepatic impairment on the pharmacokinetics of nefazodone and two of its metabolites after single and multiple oral doses

Summary— The pharmacokinetics of nefazodone, a new antidepressant, and two of its active metabolites, hydroxynefazodone and m-chlorophenylpiperazine, were determined after single and repeated oral escalating doses of 50, 100 and 200 mg, in healthy volunteers ( n = 13) and patients with mild ( n = 13) or severe ( n = 6) hepatic impairment. All subjects were classified according to their dextromethorphan oxidation capacity. In healthy volunteers, nefazodone was rapidly absorbed after which the plasma concentrations declined with an apparent elimination half-life ranging from 2.7 ± 1.7 h to 10.2 ± 4.4 h according to the dosage. Hydroxynefazodone appeared rapidly in plasma and its time-course (half-life ranging 1.4 ± 0.9 h to 6.5 ± 1.6 h) paralleled that of nefazodone, while mCPP showed low and variable concentrations. The disproportionately longer half-life and more markedly increased C_max and AUC_0–48 which was observed with dosage and treatment duration, and moreover AUC_0–12 at steady state significantly higher ( P < 0.05) than AUC_0–∞ after single dose demonstrated the non-linearity of the pharmacokinetics of nefazodone and hydroxynefazodone. The constant molar AUC_0–48 hydroxy-nefazodone/nefazodone ratio (0.32 ± 0.04) and the close correlation ( r ² = 0.95) between kinetic parameters of nefazodone and hydroxynefazodone suggest that nefazodone hydroxylation is not a saturable process. The kinetics of nefazodone and metabolites were significantly affected by severe but not by mild liver insufficiency. As a consequence, on a pharmacokinetic basis nefazodone should be used with caution in severely hepatic impaired patients.