Nefazodone

Nefazodone is an antidepressant for oral administration with a chemical structure unrelated to selective serotonin reuptake inhibitors, tricyclics, tetracyclics, or monoamine oxidase inhibitors (MAOI).

Nefazodone is a synthetically derived phenylpiperazine antidepressant.

The mechanism of action of nefazodone, as with other antidepressants, is unknown.

Preclinical studies have shown that nefazodone inhibits neuronal uptake of serotonin and norepinephrine.

Nefazodone occupies central 5-HT₂ receptors at nanomolar concentrations, and acts as an antagonist at this receptor. Nefazodone was shown to antagonize alpha₁-adrenergic receptors, a property which may be associated with postural hypotension. In vitro binding studies showed that nefazodone had no significant affinity for the following receptors: alpha₂ and beta adrenergic, 5-HT_1A, cholinergic, dopaminergic, or benzodiazepine

Nefazodone hydrochloride is rapidly and completely absorbed but is subject to extensive metabolism, so that its absolute bioavailability is low, about 20%, and variable. Peak plasma concentrations occur at about one hour and the half-life of nefazodone is 2–4 hours.

Both nefazodone and its pharmacologically similar metabolite, hydroxynefazodone, exhibit nonlinear kinetics for both dose and time, with AUC and C_max increasing more than proportionally with dose increases and more than expected upon multiple dosing over time, compared to single dosing. For example, in a multiple-dose study involving BID dosing with 50, 100, and 200 mg, the AUC for nefazodone and hydroxynefazodone increased by about 4-fold with an increase in dose from 200 to 400 mg per day; C_max increased by about 3-fold with the same dose increase. In a multiple-dose study involving BID dosing with 25, 50, 100, and 150 mg, the accumulation ratios for nefazodone and hydroxynefazodone AUC, after 5 days of BID dosing relative to the first dose, ranged from approximately 3 to 4 at the lower doses (50–100 mg/day) and from 5 to 7 at the higher doses (200–300 mg/day); there were also approximately 2- to 4-fold increases in C_max after 5 days of BID dosing relative to the first dose, suggesting extensive and greater than predicted accumulation of nefazodone and its hydroxy metabolite with multiple dosing. Steady-state plasma nefazodone and metabolite concentrations are attained within 4 to 5 days of initiation of BID dosing or upon dose increase or decrease.

Nefazodone is extensively metabolized after oral administration by n-dealkylation and aliphatic and aromatic hydroxylation, and less than 1% of administered nefazodone is excreted unchanged in urine. Attempts to characterize three metabolites identified in plasma, hydroxynefazodone (HO-NEF), metachlorophenylpiperazine (mCPP), and a triazole-dione metabolite, have been carried out. The AUC (expressed as a multiple of the AUC for nefazodone dosed at 100 mg BID) and elimination half-lives for these three metabolites were as follows:

HO-NEF possesses a pharmacological profile qualitatively and quantitatively similar to that of nefazodone. mCPP has some similarities to nefazodone, but also has agonist activity at some serotonergic receptor subtypes. The pharmacological profile of the triazole-dione metabolite has not yet been well characterized. In addition to the above compounds, several other metabolites were present in plasma but have not been tested for pharmacological activity

After oral administration of radiolabeled nefazodone, the mean half-life of total label ranged between 11 and 24 hours. Approximately 55% of the administered radioactivity was detected in urine and about 20–30% in feces.

Distribution

Nefazodone is widely distributed in body tissues, including the central nervous system (CNS). In humans the volume of distribution of nefazodone ranges from 0.22 to 0.87 L/kg.

Protein Binding

At concentrations of 25–2500 ng/mL nefazodone is extensively (>99%) bound to human plasma proteins in vitro. The administration of 200 mg BID of nefazodone for 1 week did not increase the fraction of unbound warfarin in subjects whose prothrombin times had been prolonged by warfarin therapy to 120-150% of the laboratory control. While nefazodone did not alter the in vitro protein binding of chlorpromazine, desipramine, diazepam, diphenylhydantoin, lidocaine, prazosin, propranolol, or verapamil, it is unknown whether displacement of either nefazodone or these drugs occurs in vivo. There was a 5% decrease in the protein binding of haloperidol; this is probably of no clinical significance.

Effect of Food

Food delays the absorption of nefazodone and decreases the bioavailability of nefazodone by approximately 20%.

Renal Disease

In studies involving 29 renally impaired patients, renal impairment (creatinine clearances ranging from 7 to 60 mL/min/1.73m²) had no effect on steady-state nefazodone plasma concentrations.

Liver Disease

In a multiple-dose study of patients with liver cirrhosis, the AUC values for nefazodone and HO-NEF at steady state were approximately 25% greater than those observed in normal volunteers.

Age/Gender Effects

After single doses of 300 mg to younger (18–45 years) and older patients (>65 years), C_max and AUC for nefazodone and hydroxynefazodone were up to twice as high in the older patients. With multiple doses, however, differences were much smaller, 10–20%. A similar result was seen for gender, with a higher C_max and AUC in women after single doses but no difference after multiple doses.

Treatment with nefazodone should be initiated at half the usual dose in elderly patients, especially women, but the therapeutic dose range is similar in younger and older patients.