A Study of the Effect of Age and Gender on the Pharmacokinetics of Nefazodone After Single and Multiple Doses

Abstract

The single-dose (S-D) and steady-state (S-S) pharmacokinetics of nefazodone (NEF) and two of its pharmacologically active metabolites, hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP), in healthy elderly (> 65 years) men and women (N = 12 each) were compared with those in healthy younger (18-40 years) men and women (N = 12 each). All subjects were classified as extensive metabolizers of dextromethorphan (cytochrome P4502D6). Subjects were administered a 300-mg dose of nefazodone hydrochloride for the evaluation of S-D pharmacokinetics. For the evaluation of S-S pharmacokinetics, 300-mg doses of NEF were administered twice daily (every 12 hours) for 8 days (single morning dose on day 8). Serial blood samples were collected after the single dose and the morning dose on day 8 of the twice-daily administration; a blood sample for trough level was collected from each subject just before the morning dose on days 2 to 8 of the twice-daily dosing to assess the attainment of steady state. Plasma samples were assayed for NEF, HO-NEF, and mCPP by a specific, validated high-performance liquid chromatography assay. After a single dose of NEF, the mean peak concentrations in plasma and the area under the curves (AUC) for NEF and HO-NEF were about twofold higher in elderly versus young subjects, but mean AUCs for mCPP were similar. Levels in plasma for NEF, HO-NEF, and mCPP reached steady state by day 3 of multiple dosing. At steady state, exposure to NEF and HO-NEF, based on AUC(TAU) values, was quite variable among age/gender groups but on the average was about 50% higher in elderly women compared with the other three groups of subjects; the exposure to mCPP at steady state was similar in elderly and young subjects. Because all subjects were extensive metabolizers, the effect of gender or age on the pharmacokinetics of NEF and its metabolites in poor metabolizers is not known. There were no serious or unexpected adverse experiences observed in this study. Assuming that similar systemic exposure to NEF and its active metabolites will result in similar therapeutic effects in young and elderly individuals, the difference in systematic exposure to NEF and HO-NEF in elderly subjects suggests that NEF treatment should be initiated at half the usual dose with titration upward and that the usual precautions exercised in treating elderly patients should be used.

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…For hydroxynefazodone, it can be estimated that it has approximately ;25% of the activity of nefazodone itself. Protein binding data for mCPP is available in rat (f u = 0.7), and if the value in human is similar, it would suggest that mCPP could have profound activity in humans [maximum plasma concentration (C max ) = 0.5 mM; Barbhaiya et al, 1996] including activity at serotonin and norepinephrine reuptake transporters (Owens et al, 1997).…”

Single-Dose Pharmacokinetics of the Renin Inhibitor ACT-077825 in Elderly and Young Subjects of Both Sexes

“…It has been shown that ACT-077825 is a substrate of CYP3A4 [9,19] and it was reported that the clearance of many CYP3A substrates may be reduced with age, but no sex-related differences in clearance have been reported for these drugs [20]. However, the exposure to nefazodone, a substrate and inhibitor of CYP3A4, is 50% higher in elderly women compared to young subjects or elderly men [21]. It has been hypothesized that sex-related differences in the clearance of CYP3A4 substrates may be caused by P-glycoprotein [22].…”

Clinical trials of potential antidepressants: to what extent are the elderly represented: a review

“…A study to test the antidepressant suitability of sertraline in the elderly was conducted in healthy subjects aged 50 to 67 years (Mattila et al, 1988). Pharmacokinetic studies comparing young versus elderly subjects were conducted on nefazodone, with ages ranging from 65 to 80 years (Barbhaiya et al, 1995a;Barbhaiya et al, 1996b) and paroxetine, 64 to 78 years (Bayer et al, 1989). A review on the clinical pharmacology of fluoxetine reported a study on apparently healthy elderly subjects aged 65 to 77 years (Lemberger et al, 1985).…”