R-trihexyphenidyl for treatment of movement disorders
AssigneeThe Children's Mercy Hospital
InventorsRose GELINEAU-MOREL, James Steven LEEDER, Paul C. TOREN
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Abstract
Compositions and methods for selective targeting of M1 and/or M4 muscarinic receptors, compositions and methods for treating movement disorders, such as dystonia, with improved formulations of trihexyphenidyl, and in particular, compositions comprising high chiral purity R-trihexyphenidyl or enantiomerically enriched R-trihexyphenidyl.
Claims25
A therapeutic composition comprising enantiomerically enriched R-trihexyphenidyl or a pharmaceutically acceptable salt thereof, dispersed in a pharmaceutically acceptable carrier.
A method of selectively targeting M1 and/or M4 muscarinic receptors in a subject in need thereof, the method comprising administering a therapeutically effective amount of enantiomerically enriched R-trihexyphenidyl or pharmaceutically acceptable salt thereof to the subject, wherein the R-trihexyphenidyl selectively binds to M1 and/or M4 in the subject.
An improved method for treating movement disorders in a subject in need thereof who is a poor CYP2D6 or CYP3A4/CYP3A5 metabolizer, the method comprising:
- obtaining the CYP450 metabolic phenotype of the subject, and
- administering a therapeutically effective amount of enantiomerically enriched R-trihexyphenidyl or a pharmaceutically acceptable salt thereof to the subject wherein the subject is a CYP2D6 or CYP3A4/CYP3A5 poor metabolizer.
An improved method for treating movement disorders in a subject in need thereof who is a CYP2C19 poor metabolizer, the method comprising:
- obtaining the CYP450 metabolic phenotype of the subject, and
- administering a therapeutically effective amount of enantiomerically enriched R-trihexyphenidyl or a pharmaceutically acceptable salt thereof to the subject wherein the subject is a CYP2C19 poor metabolizer, wherein said therapeutically effect amount is a low dose of said R-trihexyphenidyl as compared to a dose recommended in the clinical guidelines for trihexyphenidyl.
An improved method for treating movement disorders in a subject who is a poor CYP2D6 or CYP3A4/CYP3A5 metabolizer to minimize side effects, the method comprising:
- obtaining the CYP450 metabolic phenotype of the subject, and
- decreasing an initial dose of a racemic mixture of trihexyphenidyl or a pharmaceutically acceptable salt to less than 1 mg per day and administering to the subject wherein the subject is a CYP2D6 or CYP3A4/CYP3A5 poor metabolizer, or
- increasing an initial dose of a racemic mixture of trihexyphenidyl or a pharmaceutically acceptable salt to more than 6 mg per day and administering to the subject wherein the subject is a CYP2D6 or CYP3A4/CYP3A5 normal or ultrarapid metabolizer,
- wherein the initial dose is based upon an initial dose recommended in the clinical guidelines for trihexyphenidyl.
A method of administering an initial dose of a M1 and/or M4 muscarinic receptor inhibitor to a subject in need thereof, the initial dose based upon an initial dose recommended in the clinical guidelines for the inhibitor, the method comprising:
- obtaining the subject's genotype for a panel of cytochrome P450 enzymes comprising at least CYP2D6 and/or CYP2C19 alleles, wherein the subject is assigned a metabolic phenotype selected from poor metabolizer, intermediate metabolizer, or ultrarapid metabolizer for each enzyme based upon the number of functional alleles for each cytochrome P450 gene;
- administering to the patient an initial dose of the inhibitor, wherein said initial dose is:
- (a) an initial dose that is half the initial dose recommended in the clinical guidelines if the metabolic phenotype is one or more of CYP2D6 poor metabolizer, CYP2D6 intermediate metabolizer, or CYP2C19 poor metabolizer;
- or
- (b) an initial dose that is the same or higher than the initial dose recommended in the clinical guidelines if the metabolic phenotype is one or more of CYP2D6 ultrarapid metabolizer or CYP2C19 ultrarapid metabolizer;
- and
- wherein the inhibitor is selected from the group consisting of a racemic mixture of trihexyphenidyl, enantiomerically enriched R-trihexyphenidyl, and pharmaceutically acceptable salts thereof.
A method of reducing side effects from an initial dose of a M1 and/or M4 muscarinic receptor inhibitor in a subject in need thereof, the initial dose based upon an initial dose recommended in clinical guidelines for the inhibitor, the method comprising:
- obtaining the subject's genotype for a panel of cytochrome P450 comprising at least CYP2D6 alleles, wherein the subject is assigned a metabolic phenotype selected from poor metabolizer, intermediate metabolizer, or ultrarapid metabolizer for each enzyme based upon the number of functional alleles for CYP2D6;
- administering to the patient an initial dose of the inhibitor, wherein said initial dose is:
- (a) an initial dose that is half the initial dose recommended in the clinical guidelines if the metabolic phenotype is of a CYP2D6 poor metabolizer or CYP2D6 intermediate metabolizer;
- or
- (b) an initial dose that is the same or higher than the initial dose recommended in the clinical guidelines if the metabolic phenotype is of a CYP2D6 ultrarapid metabolizer;
- and
- wherein the inhibitor is a racemic mixture of trihexyphenidyl or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.