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Single‐ and multiple‐dose pharmacokinetics of nefazodone in patients with hepatic cirrhosis
Author(s) -
Barbhaiya Rashmi H.,
Shukla Umesh A.,
Natarajan Chandra S.,
Behr Douglas A.,
Greene Douglas S.,
Sainati Stephen M.
Publication year - 1995
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/0009-9236(95)90051-9
Subject(s) - nefazodone , pharmacokinetics , cirrhosis , medicine , dosing , gastroenterology , endocrinology , pharmacology , receptor , serotonin , fluoxetine
Objective To compare the single‐ and multiple‐dose pharmacokinetics of nefazodone and its three pharmacologically active metabolites, hydroxynefazodone, m ‐chlorophenylpiperazine, and triazoledione, in patients with biopsy‐proven cirrhosis and age‐, sex‐, and weight‐matched healthy volunteers. Methods Subjects received a single 100 mg dose of nefazodone on day 1 followed by 100 mg nefazodone every 12 hours on days 3 through 10. Serial blood samples were collected on days 1 and 10; blood samples for trough levels were also collected just before the morning doses on days 7, 8, and 9. Plasma samples were assayed for nefazodone and its metabolites by validated chromatographic methods. Results The blood samples for trough levels indicated that, regardless of hepatic function, steady state for nefazodone and its metabolites was achieved by the fourth day of every‐12‐hour dosing. Subjects with liver cirrhosis had about a two‐fold greater systemic exposure to nefazodone and hydroxy‐nefazodone compared with normal subjects after a single dose of nefazodone, the difference decreasing to approximately 25% at steady state. Exposure to m ‐chlorophenylpiperazine was twofold to threefold greater and exposure to triazoledione was similar in patients with cirrhosis after a single dose of nefazodone and at steady state. There were no serious or unexpected adverse events observed in this study. Conclusions These findings indicate that, although no untoward accumulation is anticipated compared with patients with normal hepatic function, patients with hepatic impairment may be exposed to higher concentrations of nefazodone and its metabolites than would subjects with normal hepatic function. Consequently, a lower daily dose of nefazodone should be considered when treating patients with impairment of hepatic function. Clinical Pharmacology & Therapeutics (1995) 58 , 390–398; doi: