Iloperidone

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

Iloperidone acts as an antagonist with high (nM) affinity binding to serotonin 5-HT_2A, dopamine D₂ and D₃ receptors, and norepinephrine NE_α1 receptors (K_i values of 5.6, 6.3, 7.1, and 0.36 nM, respectively). Iloperidone has moderate affinity for dopamine D₄, and serotonin 5-HT₆ and 5-HT₇ receptors (K_i values of 25, 43, and 22, nM respectively), and low affinity for the serotonin 5-HT_1A, dopamine D₁, and histamine H₁ receptors (K_i values of 168, 216, and 437 nM, respectively). Iloperidone has no appreciable affinity (K_i>1000 nM) for cholinergic muscarinic receptors. The affinity of iloperidone metabolite P88 is generally equal to or less than that of the parent compound, while the metabolite P95 only shows affinity for 5-HT_2A (K_i value of 3.91) and the NE_α1A, NE_α1B, NE_α1D, and NE_α2C receptors (K_i values of 4.7, 2.7, 8.8, and 4.7 nM respectively).

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 (T_max) 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 C_max or AUC of iloperidone, P88, or P95, but delayed T_max by 1 hour for iloperidone, 2 hours for P88 and 6 hours for P95. Iloperidone 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.

Specific Populations

Patients with renal impairment

Renal impairment (creatinine clearance <30 mL/min) had minimal effect on C_max 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.

Effect of Smoking

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

Drug interactions studies

CYP2D6 and CYP3A4 inhibitors

The effects of fluoxetine and ketoconazole on the exposures of iloperidone, P88, and P95 are summarized in Figure 1.

Figure 1. Effect of CYP3A4 and CYP2D6 Inhibitors on the Pharmacokinetics of iloperidone and its Metabolites:

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.

Fluoxetine: Coadministration of fluoxetine (20 mg twice daily for 21 days), a potent inhibitor of CYP2D6, with a single 3 mg dose of iloperidone to 23 healthy volunteers, ages 29-44 years, who were classified as CYP2D6 extensive metabolizers, increased the AUC of iloperidone and its metabolite P88, by about 2- to 3- fold, and decreased the AUC of its metabolite P95 by one-half.

Paroxetine: Coadministration of paroxetine (20 mg/day for 5-8 days), a potent inhibitor of CYP2D6, with multiple doses of iloperidone (8 or 12 mg twice daily) to patients with schizophrenia ages 18-65 years resulted in increased mean steady-state peak concentrations of iloperidone and its metabolite P88, by about 1.6 fold, and decreased mean steady-state peak concentrations of its metabolite P95 by one-half.

Paroxetine and Ketoconazole: Coadministration of paroxetine (20 mg once daily for 10 days), a CYP2D6 inhibitor, and ketoconazole (200 mg twice daily) with multiple doses of iloperidone (8 or 12 mg twice daily) to patients with schizophrenia ages 18-65 years resulted in a 1.4 fold increase in steady-state concentrations of iloperidone and its metabolite P88 and a 1.4 fold decrease in the P95 in the presence of paroxetine.

Dextromethorphan: A study in healthy volunteers showed that changes in the pharmacokinetics of dextromethorphan (80 mg dose) when a 3 mg dose of iloperidone was co-administered resulted in a 17% increase in total exposure and a 26% increase in the maximum plasma concentrations C_max of dextromethorphan. Thus, an interaction between iloperidone and other CYP2D6 substrates is unlikely.

Fluoxetine: A single 3 mg dose of iloperidone had no effect on the pharmacokinetics of fluoxetine (20 mg twice daily).

Midazolam (a sensitive CYP 3A4 substrate): A study in patients with schizophrenia showed a less than 50% increase in midazolam total exposure at iloperidone steady state (14 days of oral dosing at up to 10 mg iloperidone twice daily) and no effect on midazolam C_max. Thus, an interaction between iloperidone and other CYP3A4 substrates is unlikely.

In vitro studies

Based on the in vitro data, iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely.

In vitro studies in human liver microsomes showed that iloperidone does not substantially inhibit the metabolism of drugs metabolized by the following cytochrome P450 isozymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, or CYP2E1. Furthermore, in vitro studies in human liver microsomes showed that iloperidone does not have enzyme inducing properties, specifically for the following cytochrome P450 isozymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5.

Transporter Interaction: Iloperidone and P88 are not substrates of P-gp and iloperidone is a weak P-gp inhibitor.