title: Single-dose pharmacokinetics of nefazodone in healthy young and elderly subjects and in subjects with renal or hepatic impairment.
abstract: The single-dose pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were examined in 12 healthy younger subjects < or = 55 years of age (YNG), 12 elderly subjects > or = 65 years of age (ELD), 12 patients with biopsy proven hepatic cirrhosis (HEP) and 12 patients with moderate renal impairment (REN), ClCR 20-60 ml.min-1. The study was of parallel group design, with each of the four subject groups receiving escalating single oral doses of 50, 100 and 200 mg of nefazodone at 1 week intervals. Serial blood samples for pharmacokinetic analysis were collected for 48 h following each dose and plasma samples were assayed for NEF, HO-NEF and mCPP by a validated HPLC method. Single oral doses up to 200 mg of nefazodone were well tolerated by all subjects. Maximum plasma levels of NEF and HO-NEF were generally attained within 1 h after administration of nefazodone. HO-NEF and mCPP plasma levels were about 1/3 and < 1/10 those of NEF, respectively. There were no apparent gender-related pharmacokinetic differences in any group of subjects. NEF and HO-NEF pharmacokinetics were dose dependent in all four subject groups; a superproportional increase in AUC and an increase in t1/2 with increasing dose was obtained, indicative of nonlinear pharmacokinetics. Relative to normal subjects, elderly and cirrhotic subjects exhibited increased systemic exposure to NEF and HO-NEF, as reflected by AUC, at all doses of nefazodone; subjects with moderate renal impairment did not. Elderly and cirrhotic patients may require lower doses of NEF to achieve and maintain therapeutic effectiveness.
authors.affiliation: Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Barbhaiya
authors.forename: U A
authors.initials: UA
authors.lastname: Shukla
authors.forename: D S
authors.initials: DS
authors.lastname: Greene
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000367:Age Factors; D000368:Aged; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000097:blood / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000097:blood / Q000378:metabolism*; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*
chemical_list: D000928:Antidepressive Agents; D010879:Piperazines; D017366:Serotonin Receptor Agonists; D014230:Triazoles; C092333:hydroxynefazodone; C051752:nefazodone; C015068:1-(3-chlorophenyl)piperazine