A STUDY OF THE EFFECT OF AGE AND GENDER ON THE PHARMACOKINETICS OF NEFAZODONE AFTER SINGLE AND MULTIPLE DOSES

The single-dose (S-D) and steady-state (S-S) pharmacokinetics of nefaz odone (NEF) and two of its pharmacologically active metabolites, hydro xynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP), in healthy elderly (>65 years) men and women (N = 12 each) were compared with tho se in healthy younger (18-40 years) men and women (N = 12 each). All s ubjects were classified as extensive metabolizers of dextromethorphan (cytochrome P4502D6). Subjects were administered a 300-mg dose of nefa zodone hydrochloride for the evaluation of S-D pharmacokinetics. For t he evaluation of S-S pharmacokinetics, 300-mg doses of NEF were admini stered 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 th e 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-NE F, and mCPP by a specific, validated high-performance liquid chromatog raphy assay. After a single dose of NEF, the mean peak concentrations in plasma and the area under the curves (AUG) for NEF and HO-NEF were about twofold higher in elderly versus young subjects, but mean AUCs f or mCPP were similar. Levels in plasma for NEF, HO-NEF, and mCPP reach ed 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 t o mCPP at steady state was similar in elderly and young subjects. Beca use all subjects were extensive metabolizers, the effect of gender or age on the pharmacokinetics of NEF and its metabolites in poor metabol izers is not known. There were no serious or unexpected adverse experi ences observed in this study. Assuming that similar systemic exposure to NEF and its active metabolites will result in similar therapeutic e ffects in young and elderly individuals, the difference in systematic exposure to NEF and HO-NEF in elderly subjects suggests that NEF treat ment should be initiated at half the usual dose with titration upward and that the usual precautions exercised in treating elderly patients should be used.