Methods for the administration of iloperidone

a technology of iloperidone and administration method, which is applied in the direction of biocide, drug composition, cardiovascular disorder, etc., can solve problems such as problems or dangers, and achieve the effect of reducing the dose of iloperidone administered to the patien

Inactive Publication Date: 2010-03-11
VANDA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]Another aspect of the invention provides a method of treating a patient with iloperidone or an active metabolite thereof or a pharmaceutically acceptable salt of either comprising the steps of determining whether the patient is being administered a CYP2D6 inhibitor and reducing the dosage of drug if the patient is being administered a CYP2D6 inhibitor.
[0013]Another aspect of the invention provides a method for determining whether a patient is at risk for prolongation of his or her QTc interval due to iloperidone administration comprising the step of: determining a patient's CYP2D6 metabolizer status by either determining the patient's CYP2D6 genotype or CYP2D6 phenotype. In the case that a patient is determined to be at risk for prolongation of his or her QTc interval, the dose of iloperidone administered to the patient may be reduced.

Problems solved by technology

This can prove problematic or dangerous where an increased concentration of a non-metabolized drug or its metabolites is capable of producing unwanted physiological effects.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0023]Blood samples for pharmacogenetic analysis were collected at screening. Two polymorphisms previously associated with poor metabolizing status were genotyped in the CYP2D6 locus, and 251 genotypes were collected. The individual genotypes were studied for detection of association between genotype class and concentrations of iloperidone and its metabolites P88 and P95. The functional effect of the polymorphisms was also evaluated by analyzing the effect of the addition of the CYP2D6 inhibitor paroxetine on the concentrations of the parent drug and its metabolites.

[0024]The research leading to the present invention identified a significant association between CYP2D6 genotype and concentrations of P88 before the addition of inhibitors as well as the effect of this association on QTc prolongation.

[0025]Iloperidone is a substrate for two P450 enzymes; CYP2D6 and CYP3A4. Most metabolic clearance of iloperidone depends on these two enzymes. CYP2D6 catalyzes hydroxylation of the pendant...

example 2

[0053]A second study extended the pharmacogenomic assessment of iloperidone response by genotyping additional CYP2D6 variants which lead to the production of a non-functional protein or reduced enzymatic activity.

[0054]Six of the variants have been shown to result in the absence of a functional enzyme, either because of a deletion of the gene (as in the CYP2D6*5 polymorphism), a frameshift (*3 and *6), a splicing error (*4), or a truncated or abnormal protein (*7 and *8). Five other polymorphisms were genotyped that resulted in the production of a functional protein that was shown to have a significantly decreased enzymatic activity on various compounds such as debrisoquine or sparteine (*9, *10, *17, *41), or only a modest reduction in activity (*2). The actual impact of these individual polymorphisms on the enzyme vary from compound to compound, and the presence of several of them in the same protein can further reduce the CYP2D6 activity.

Methods

A. Samples

[0055]From the 300 iloper...

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Abstract

The present invention relates to methods for the identification of genetic polymorphisms that may be associated with a risk for QT prolongation after treatment with iloperidone and related methods of administering iloperidone to patients with such polymorphisms.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation-in-part of co-pending U.S. patent application Ser. No. 11 / 576,178, filed Mar. 28, 2007, which claims the benefit of Provisional Patent Application Ser. No. 60 / 614,798, filed Sep. 30, 2004, and is currently pending and hereby incorporated herein.BACKGROUND OF THE INVENTION[0002]Several genes associated with drug metabolism have been found to be polymorphic. As a result, the abilities of individual patients to metabolize a particular drug may vary greatly. This can prove problematic or dangerous where an increased concentration of a non-metabolized drug or its metabolites is capable of producing unwanted physiological effects.[0003]The cytochrome P450 2D6 gene (CYP2D6), located on chromosome 22, encodes the Phase I drug metabolizing enzyme debrisoquine hydroxylase. A large number of drugs are known to be metabolized by debrisoquine hydroxylase, including many common central nervous system and cardiovascula...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/454C12Q1/68A61P25/00
CPCA61K31/454A61K31/496C12Q1/6883A61K31/4525A61K31/135A61K2300/00A61P25/00A61P25/18A61P25/22A61P25/24A61P9/06C12Q2600/106C12Q2600/156
Inventor WOLFGANG, CURTPOLYMEROPOULOS, MIHAELLAVEDAN, CHRISTIANVOLPI, SIMONA
Owner VANDA PHARMA INC
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