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

Abstract

The pharmacokinetics of nefazodone, a new antidepressant, and two of its active metabolites, hydroxy-nefazodone 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. Hydroxy-nefazodone 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 Cmax and AUC0-48 which was observed with dosage and treatment duration, and moreover AUC0-12 at steady state significantly higher (P < 0.05) than AUC0-infinity after single dose demonstrated the non-linearity of the pharmacokinetics of nefazodone and hydroxy-nefazodone. The constant molar AUC0-48 hydroxy-nefazodone/nefazodone ratio (0.32 +/- 0.04) and the close correlation (r2 = 0.95) between kinetic parameters of nefazodone and hydroxy-nefazodone 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.