Iloperidone 1 mg · Tablets

The mechanism of action of iloperidone in schizophrenia and bipolar I disorder is unknown. However, the efficacy of iloperidone could be mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5-HT2) antagonism. Iloperidone forms an active metabolite, P88, that has an in vitro receptor binding profile similar to the parent drug.

The pharmacokinetics of iloperidone is more than dose proportional. Steady-state concentrations are attained within 3 to 4 days of dosing. Iloperidone accumulation is predictable from single-dose pharmacokinetics.

Absorption — Iloperidone is well absorbed after administration of the tablet with time to peak plasma concentrations (Tmax) occurring within 2 to 4 hours. The relative bioavailability of the tablet formulation compared to oral solution is 96%.

Effect of Food — Administration of iloperidone with a standard high-fat meal did not significantly affect the Cmax or AUC of iloperidone, P88, or P95, but delayed Tmax by 1 hour for iloperidone, 2 hours for P88 and 6 hours for P95. FANAPT can be administered without regard to meals.

Distribution — Iloperidone has an apparent volume of distribution of 1340-2800 L. At therapeutic concentrations, the unbound fraction of iloperidone in plasma is ~3% and of each metabolite (P88 and P95) it is ~8%.

Elimination — The observed mean elimination half-lives for iloperidone, P88, and P95 in CYP2D6 extensive metabolizers (EM) are 18, 26, and 23 hours, respectively, and in poor metabolizers (PM) are 33, 37, and 31 hours, respectively.

Iloperidone has an apparent clearance (clearance / bioavailability) of 47 to 102 L/h.

Metabolism — Elimination of iloperidone is mainly through hepatic metabolism. Iloperidone is metabolized primarily by 3 biotransformation pathways: carbonyl reduction, hydroxylation (mediated by CYP2D6) and O-demethylation (mediated by CYP3A4). There are 2 predominant iloperidone metabolites, P95 and P88. The iloperidone metabolite P95 represents 47.9% of the AUC of iloperidone and its metabolites in plasma at steady-state for extensive metabolizers (EM) and 25% for poor metabolizers (PM). The active metabolite P88 accounts for 19.5% and 34.0% of total plasma exposure in EM and PM, respectively.

Approximately 7% - 10% of Caucasians and 3% - 8% of black/African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are intermediate, extensive, or ultrarapid metabolizers.

Excretion — The bulk of the radioactive materials were recovered in the urine (mean 58.2% and 45.1% in EM and PM, respectively), with feces accounting for 19.9% (EM) to 22.1% (PM) of the dosed radioactivity.

Patients with Renal Impairment — Renal impairment (creatinine clearance <30 mL/min) had minimal effect on Cmax of iloperidone (given in a single dose of 3 mg) and its metabolites P88 and P95 in any of the 3 analytes measured. AUC0–∞ was increased by 24%, decreased by 6%, and increased by 52% for iloperidone, P88 and P95, respectively, in subjects with renal impairment.

Patients with Hepatic Impairment — In adult subjects with mild hepatic impairment, no relevant difference in pharmacokinetics of iloperidone, P88 or P95 (total or unbound) was observed compared to healthy adult controls. In subjects with moderate hepatic impairment a higher (2-fold) and more variable free exposure to the active metabolites P88 was observed compared to healthy controls, whereas exposure to iloperidone and P95 was generally similar (less than 50% change compared to control). Studies with severe liver impaired subjects have not been conducted [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].

Effect of Smoking — Based on in vitro studies utilizing human liver enzymes, FANAPT is not a substrate for CYP1A2; smoking should therefore not have an effect on the pharmacokinetics of FANAPT.

CYP2D6 and CYP3A4 Inhibitors — The effects of fluoxetine and ketoconazole on the exposures of FANAPT, P88, and P95 are summarized in Figure 1.

Ketoconazole: Co-administration of ketoconazole (200 mg twice daily for 4 days), a potent inhibitor of CYP3A4, with a 3 mg single dose of iloperidone to 19 healthy volunteers, ages 18-45 years, increased the area under the curve (AUC) of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively. Weaker inhibitors (e.g., erythromycin, grapefruit juice) have not been studied.