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: R H Barbhaiya, U A Shukla, D S Greene
• Journal: European journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 49 Issue 3 Pg. 221-8 ( 1995) ISSN: 0031-6970 [Print] Germany
• PMID: 8665999 (Publication Type: Journal Article)

Chemical References

• Antidepressive Agents
• Piperazines
• Serotonin Receptor Agonists
• Triazoles
• hydroxynefazodone
• nefazodone
• 1-(3-chlorophenyl)piperazine

Topics

• Administration, Oral
• Adult
• Age Factors
• Aged
• Antidepressive Agents (administration & dosage, adverse effects, blood, pharmacokinetics)
• Female
• Humans
• Kidney Diseases (metabolism)
• Liver Cirrhosis (metabolism)
• Male
• Middle Aged
• Piperazines (blood, metabolism)
• Serotonin Receptor Agonists (blood, metabolism)
• Triazoles (administration & dosage, adverse effects, blood, metabolism, pharmacokinetics)