Iloperidone Pharmacokinetics

Source: Drug labeling information submitted to the Food and Drug Administration (FDA), updated by the National Library of Medicine (NLM).

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. Steady-state concentrations are attained within 3-4 days of dosing. Iloperidone accumulation is predictable from single-dose pharmacokinetics. The pharmacokinetics of iloperidone is more than dose proportional. Elimination of iloperidone is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4.

Absorption

Iloperidone is well absorbed after administration of the tablet with peak plasma concentrations occurring within 2 to 4 hours; while the relative bioavailability of the tablet formulation compared to oral solution is 96%. 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 clearance (clearance / bioavailability) of 47 to 102 L/h, with an apparent volume of distribution of 1340-2800 L. At therapeutic concentrations, iloperidone and its metabolites are ~95% bound to serum proteins.

Metabolism and Elimination

Iloperidone is metabolized primarily by three biotransformation pathways: carbonyl reduction, hydroxylation (mediated by CYP2D6) and O-demethylation (mediated by CYP3A4). There are two 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. Co-administration of FANAPT with known strong inhibitors of CYP2D6 like fluoxetine results in a 2.3 fold increase in iloperidone plasma exposure, and therefore one-half of the FANAPT dose should be administered.

Similarly, PMs of CYP2D6 have higher exposure to iloperidone compared with EMs and PMs should have their dose reduced by one-half. Laboratory tests are available to identify CYP2D6 PMs.

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.

Transporter Interaction

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

Related Iloperidone Information

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