WO2021146425A1 - Methods of treating acute muscle spasms - Google Patents

Abstract

The present disclosure provides methods for safely administering tolperisone or a pharmaceutically acceptable salt thereof, in patients who are CYP2D6 poor metabolizers as well as patients who are concomitantly administered a cytochrome P450 2D6 (CYP2D6) inhibitor or a cytochrome P450 2C19 (CYP2C19) inhibitor.

Description

METHODS OF TREATING ACUTE MUSCLE SPASMS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S Provisional Application Serial No. 62/961,011, filed on January 14, 2020, the contents of which is hereby incorporated by reference in its entirety for all purposes.

BACKGROUND

[0002] Tolperisone is a centrally-acting muscle relaxant that has been used for the symptomatic treatment of spasticity and muscle spasm (Martindale, The Extra Pharmacopoeia, 30th ed., p. 1211). Tolperisone has also been used in the treatment of conditions, which include dysmenorrhea, climacteric complaints, lockjaw, and neurolatyrism.

[0003] The chemical structure of tolperisone is shown below.

[0004] As can be seen by the foregoing structure, tolperisone contains a chiral center (as indicated by the asterisk). The chiral separation of tolperisone into its R(-) and S(+) enantiomers has been described (See, for example, JP-A-53-40779).

[0005] Racemic tolperisone is commercially available as the hydrochloride salt and is sold under trade names such as Mydeton^®, Mydocalm^®, Midocalm^® and Muscalm^®.

[0006] Tolperisone has been shown to exhibit membrane-stabilizing effects in the central and peripheral nervous system (Ono, EL, eta/., ./. Pharmacobio. Dynam. 1984, 7, 171-178). Tolperisone hydrochloride is used for improving not only different symptoms related to spastic paralysis, but also for improving muscle tone, which originates from diseases or conditions such as cervical syndrome, inflammation of the joints, and back pain. The use of tolperisone for treating neuropathic pain and pain associated with various nervous system disorders has also been described (see, for example, U.S. Patent Application No. 2006/0004050).

[0007] The present disclosure relates to safe concomitant administration of tolperisone and CYP2D6 inhibitor or a cytochrome P450 2C19 inhibitor. The present disclosure further relates to methods of safely administering tolperisone in a patient who is a CYP2D6 poor metabolizer. Thus, the present disclosure provides methods of treating muscle spasm or spastic syndrome using tolperisone in patients receiving concomitant administration of a CYP2D6 inhibitor or a cytochrome P4502C19 inhibitor, as well as patients who are CYP2D6 poor metabolizers.

SUMMARY OF THE INVENTION

[0008] In one aspect, the present disclosure provides a method of treating a patient with muscle spasm or spastic syndrome with tolperisone or a pharmaceutically acceptable salt thereof, comprising orally administering to the patient an adjusted dose of the tolperisone when the patient is receiving concomitant administration of a cytochrome P450 2D6 (“CYP2D6”) inhibitor or a cytochrome P450 2C19 (“CYP2C19”) inhibitor.

[0009] In one aspect, the present disclosure provides a method of safely administering tolperisone or a pharmaceutically acceptable salt thereof for the treatment of a patient with muscle spasm or spastic syndrome who is being administered tolperisone, the method comprising: (1) determining if the patient has taken or will take, a concomitant dose of a CYP2D6 inhibitor or a cytochrome CYP2C19 inhibitor and (2) orally administering an adjusted dose of the tolperisone when the patient is receiving a concomitant administration of a CYP2D6 inhibitor or a CYP2C19 inhibitor.

[0010] In one aspect, the present disclosure provides a method for treating a patient with muscle spasm or spastic syndrome, the method comprising: (1) administering a therapeutically effective amount of a composition comprising a daily dose of about 450 mg to 600 mg tolperisone or a pharmaceutically acceptable salt there; (2) determining if the patient is being administered a CYP2D6 inhibitor or a cytochrome CYP2C19; (3) warning of a potential drug/drug interaction due to the combination of the CYP2D6 inhibitor or a cytochrome CYP2C19 and tolperisone; and (4) recommending an adjusted dose of tolperisone. [0011] In some embodiments, the adjusted amount is reduced at least about 5% relative to the dose of the tolperisone or a pharmaceutically acceptable salt thereof the patient is normally administered (i e., the dose when the patient is not concomitantly administered a CYP2D6 inhibitor or a cytochrome CYP2C19). In some embodiments, the adjusted amount is reduced between about 5% to 50 %, relative to the dose of the tolperisone or a pharmaceutically acceptable salt thereof the patient is normally administered.

[0012] In one aspect, the present disclosure provides methods for safely administering tolperisone to patients with genetic polymorphisms that may be associated with high blood plasma exposure levels after treatment with tolperisone.

[0013] In a further aspect, the present disclosure provides a method of safely administering tolperisone or a pharmaceutically acceptable salt thereof for the treatment of muscle spasm or spastic syndrome, the method comprising: (1) determining whether the patient is a CYP2D6 poor metabolizer by determining if the patient a CYP2D6 poor metabolizer genotype; (2) if the patient has CYP2D6 poor metabolizer genotype, then orally administer a daily dose of tolperisone or salt from about 450 mg to 600 mg per day; and (3) if the patient does not have a CYP2D6 poor metabolizer genotype, then orally administer a daily dose of tolperisone or salt from about 450 mg to 600 mg per day.

[0014] In some embodiments, the muscle spasm or spastic syndrome is post-stroke spasticity.

[0015] In some embodiments, the muscle spasm or spastic syndrome is one or more acute musculoskeletal conditions.

[0016] In certain further embodiments, muscle spasm or spastic syndrome is acute muscle spasm of the neck and/or back.

[0017] In certain further embodiments, tolperisone provides relief of neck and/or back pain due to muscle spasm of acute onset.

DETAILED DESCRIPTION OF THE DRAWINGS

[0018] FIG. l is a schematic showing the study design for a Phase I trial examining the effects on pharmacokinetics of administering tolperisone hydrochloride with either fluvoxamine or paroxetine. [0019] FIG. 2A provides a graph of Mean Plasma Concentration vs. Time for tolperisone hydrochloride and tolperisone hydrochloride + fluvoxamine (Group 1) - linear (top panel) and semi logarithmic plots (bottom panel).

[0020] FIG. 2B provides a graph of Mean Plasma Concentration vs. Time for tolperisone hydrochloride and tolperisone hydrochloride + paroxetine (Group 2) - linear (top panel) and semi logarithmic plots (bottom panel).

[0021] FIG. 3 provides a schematic showing the study design for a Phase II trial assessing the efficacy of multiple doses of tolperisone hydrochloride administered TID over 14 days.

DETAILED DESCRIPTION

[0022] All publications, patents and patent applications cited herein, whether supra or infra , are hereby incorporated by reference in their entirety for all purposes.

DEFINITIONS

[0023] It must be noted that, as used in this specification, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0024] In describing and claiming the present invention, the following terminology will be used in accordance with the definitions described below.

[0025] The terms “concomitant” and “concomitantly” as used herein refers to the administration of at least two drugs to a patient wherein a second drug is administered either subsequently, simultaneously, or consequently within a time period so that the effects of the first administered drug is still operating in the patient. For example, in some embodiments, concomitant administration of the second drug occurs within one day before or after administration of the first drug (i.e., if the first drug is still operating in the patient at the time the second drug is administered).

[0026] The term “tolperisone”, as well as reference to other chemical compounds herein, includes the compound in any of its pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, and polymorphs, particular crystalline forms, as well as racemic mixtures and pure isomers of the compounds described herein, where applicable. [0027] "Pharmaceutically acceptable excipient or carrier" refers to an excipient that may optionally be included in the compositions of the invention and that causes no significant adverse toxicological effects to the patient upon administration.

[0028] "Pharmaceutically acceptable salt" includes, but is not limited to, amino acid salts, salts prepared with inorganic acids, such as chloride, sulfate, phosphate, diphosphate, bromide, and nitrate salts, or salts prepared from the corresponding inorganic acid form of any of the preceding, e.g., hydrochloride, etc., or salts prepared with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, ethyl succinate, citrate, acetate, lactate, methanesulfonate, benzoate, ascorbate, para- toluenesulfonate, palmoate, salicylate and stearate, as well as estolate, gluceptate and lactobionate salts. Similarly salts containing pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium (including substituted ammonium).

[0029] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.

[0030] "Substantially absent" or "substantially free" of a certain feature or entity means nearly totally or completely absent the feature or entity. As used herein, a tolperisone formulation that is substantially absent or substantially free of 4-MMPPO contains less than about 10 ppm 4-MMPPO.

[0031] A tolperisone composition that has been stored under "dry conditions" is one that has been stored under controlled humidity conditions (5-25 percent relative humidity) and at temperatures ranging from about 18-25°C. The tolperisone composition may be the active pharmaceutical ingredient (API), or a pharmaceutical composition (powder or the like) comprising tolperisone and one or more pharmaceutically acceptable excipients, or a finished product, for example, a capsule, tablet, etc. The composition is contained in a sealed container such as a bottle, blister, pouch, or a combination thereof. The composition may also be stored in the presence of a desiccant, such as silica, typically encased in a pack suitable for absorption of water vapor.

[0032] "Anhydrous" refers to a material that is substantially absent water.

[0033] The terms "subject", "individual" or "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, humans. [0034] Additional definitions can be found in the sections that follow.

TOLPERISONE

[0035] Tolperisone for use as part of the present disclosure may be obtained commercially, or can be synthesized by a variety of methods known in the art. See, e.g., U.S. Patent Application Publication No. 2006/0041141; Ditriech et al. (1999) J Labeled Cpd. Radiopharm , 42:1125-1134; Jap. Pat. No. 04005283 19920109; Jap. Pat. No. 54032480 19790309; Jap. Pat. No. 54036274 19790316; Jap. Pat. No. 54030178 19790306; Jap. Pat. No. 54027571 19790301; Kazuharu et al. (1994) Chem. Pharm. Bulletin 42(8) 1676; Jap. Pat. No. 20,390 (1965); and Hung. Pat. No. 144,997 (1956), each incorporated herein by reference in its entirety.

[0036] Commercial formulations of tolperisone, such as Mydeton® and Mydocalm®, and tolperisone prepared according to most known synthetic methods, possess levels of 2-methyl- 1 -(4- methylphenyl)propenone (4-MMPPO) in excess of 100 ppm. Due to the genotoxic side effects associated with 4-MMPPO, tolperisone is preferably prepared and formulated for use herein in accordance with other methods referenced and described hereinafter. Such methods produce tolperisone substantially free of 4-MMPPO.

[0037] U.S. Patent No. 9,675,598 (which is hereby incorporated by reference in its entirety for all purposes) discloses methods of detecting levels of 4-MMPPO below about 0.001% weight (10 ppm). It is believed that the method is capable of detecting levels of 4-MMPPO down to at least 0.5 ppm.

[0038] U.S. Patent No. 9,675,598 discloses methods of preparing tolperisone formulations that are substantially free of 4-MMPPO. Thus, tolperisone formulations that contain less than about 10 ppm 4-MMPPO may be prepared, for example, by recrystallization and acid treatment (see Examples 1-5 hereinafter).

[0039] Preferably, tolperisone and tolperisone compositions as described herein are stored under dry conditions. Dry conditions as used herein refers to a temperature ranging from about 18 to 23°C and a relative humidity of 5-25%. The compositions may also be stored in the presence of a desiccant, such as silica, typically encased in a pack suitable for absorption of water vapor. [0040] In a preferred embodiment, a tolperisone composition herein comprises tolperisone in the form of an acid addition salt (e.g. racemic tolperisone hydrochloride). In another preferred embodiment, a tolperisone composition herein will also comprise an additional amount of an acidic additive or excipient to establish an environment that is more acidic than that provided by tolperisone in the form of an acid addition salt. Such additives include acetic acid, succinic acid, adipic acid, propionic acid, citric acid, toluenesulfonic acid, methanesulfonic acid, and the like. Preferred acids are di-acids or greater (e.g., di-acids, tri-acids, etc.), having more than one acidic proton. Preferably, acids for use as stabilizers for compositions of tolperisone will possess a pKa of less than about 3. Preferably, the acid is anhydrous. Particularly preferred acids include citric acid and succinic acid.

[0041] Tolperisone may also be combined within a glassy matrix; glass formers are well known in the art, and may be effective in preventing chemical degradation of tolperisone, particularly degradation that results in the formation of 4-MMPPO.

TOLPERISONE USES AND TREATMENT REGIMENS

[040] Tolperisone is a centrally-acting muscle relaxant that acts on the central nervous system and is used mainly for the treatment of elevated muscle tone and tension, as well as for certain circulatory problems in the extremities. Tolperisone has been found to reduce experimental hypertonia and decerebration rigidity, as well as inhibit reticulospinal reflex facilitation without affecting cortical functions. It also improves peripheral blood flow (Toperin® Package Insert).

[041] Tolperisone is useful in treating a number of conditions. For example, tolperisone may be administered to a subject suffering from one of more of the following conditions including: muscle spasm, spastic syndromes, muscle soreness, myotonia, dysmenorrhea, climacteric complaints, lockjaw, neurolatyrism, osteoarthritis or rheumatoid arthritis (when administered in combination with a non-steroidal anti-inflammatory drug), rheumatic diseases, fibromyalgia syndrome, occupational and sport-related stress, back pain, spasticity caused by neurological diseases, multiple sclerosis, myelopathy, encephalomyelitis, stroke, muscular hypertension, muscular contracture, spinal automatism, obliterative vascular diseases (e.g., obliterative arteriosclerosis, diabetic angiopathy, obliterative thromboangitis, Raynaud's disease, diffuse scleroderma), disorders due to injured innervation of the vessels (acrocyanosis, intermittent angioneurotic dysbasis), neuropathic pain, and in individual cases, post-thrombotic venous and lymphatic circulation disorders, diabetic neuropathy, post-herpetic neuralgia, and crural ulcer (Myolax® Package insert).

[042] Subj ects to whom tolperisone may be administered include both children (aged three months to 18 years), and adults (18 years and older).

[043] In some embodiments, the one or more of the muscle conditions described herein is a muscle spasm or spastic syndrome. In certain further embodiments, the muscle spasm or spastic syndrome is post-stroke spasticity.

[044] In other embodiments, the muscle spasm or spastic syndrome is one or more acute musculoskeletal conditions. In certain further embodiments, the one or more acute musculoskeletal conditions is acute muscle spasm of the neck and/ or back.

[045] In other embodiments, the muscle spasm or spastic syndrome is muscle spasm associated with acute, painful musculoskeletal conditions.

[046] In further embodiments, tolperisone provides relief of neck and/or back pain due to muscle spasm of acute onset.

TOLPERISONE DOSES IN PATIENTS CONCOMITANTLY ADMINISTERED A CYP2D6 OR A CYP2C19 INHIBITOR

[047] In one aspect, the present disclosure relates to the discovery of drug interactions that change one of, or both, the efficacy or safety profile of tolperisone.

[048] In vitro data demonstrates that tolperisone is both a substrate for and an inhibitor of the cytochrome (CYP) P450 family of liver enzymes. Clinically relevant interactions between tolperisone hydrochloride and commonly used drugs that are inducers, substrates, or inhibitors of CYP enzyme activity cannot be excluded. Nonclinical data suggests that the systemic exposure of tolperisone and/or CYP substrates, inhibitors, or inducers may be altered by concomitant administration.

[049] In a Phase 1 drug-drug interaction study (Example 8, below), the present inventors discovered that the tolperisone plasma exposure increased approximately 2-fold following concomitant administration with paroxetine (a CYP2D6 inhibitor) and increased by 3- to 4- fold following concomitant administration with fluvoxamine (a CYP2C19 inhibitor). To achieve therapeutic benefits while minimizing the risk of adverse events, the present disclosure provides methods wherein tolperisone is administered in a reduced amount when a CYP2D6 inhibitor or CYP2C19 inhibitor is concomitantly administered. The CYP2D6 or CYP2C19 inhibitors may also be avoided or discontinued to prevent unsafe concomitant administration.

[050] The present inventors have developed methods to safely concomitantly administer tolperisone (or a pharmaceutically acceptable salt thereof) and a CYP2D6 or a CYP2C19 inhibitor by adjusting the patient’s tolperisone dose when the patient is concomitantly administered a CYP2D6 or CYP2C19 inhibitor.

[051] In some embodiments, the dose of tolperisone or pharmaceutically acceptable salt thereof with concomitant administration of the CYP2D6 inhibitor or the CYP2C19 inhibitor is about 150 mg, about 200 mg, about 250 mg, about 300 rag, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg and about 600 mg per day. In some embodiments, the dose of tolperisone or pharmaceutically acceptable salt thereof with concomitant administration of the CYP2D6 inhibitor or the CYP2C19 inhibitor is about 450 mg per day. In some embodiments, the dose of tolperisone or pharmaceutically acceptable salt thereof with concomitant administration of the CYP2D6 inhibitor or the CYP2C19 inhibitor is about 600 mg per day.

[052] In some embodiments, the present disclosure provides a method of treating muscle spasm or spastic syndrome in a patient in need thereof with tolperisone or a pharmaceutically acceptable salt thereof, the method comprising: orally administering to the patient at least a 1% decrease in an effective dosage amount of tolperisone or a pharmaceutically acceptable salt thereof when the patient is receiving a concomitant administration of a cytochrome P450 2D6 (CYP2D6) inhibitor or a cytochrome P450 2C19 (CYP2C19) inhibitor.

[053] In some embodiments, the present disclosure provides a method of treating a patient having muscle spasm associated with acute, painful musculoskeletal conditions, comprising: orally administering a dose of tolperisone or a pharmaceutically acceptable salt thereof which is less (e.g., at least 5% less) than the standard dose of tolperisone or a pharmaceutically acceptable salt thereof, when the patient is receiving a concomitant administration of a cytochrome P450 2D6 (CYP2D6) inhibitor or a cytochrome P4502C19 (CYP2C19) inhibitor, wherein the standard dose is the dose of tolperisone or a pharmaceutically acceptable salt thereof that would be recommended for a patient (e.g., an otherwise identical patient) who is not concomitantly administered a CYP2D6 inhibitor or CYP2C19 inhibitor.

[054] In some embodiments, the present disclosure provides a method of treating a patient having muscle spasm associated with acute, painful musculoskeletal conditions, comprising:

(a) administering a cytochrome P4502D6 (CYP2D6) inhibitor or a cytochrome P4502C19 (CYP2C19) inhibitor; and, concomitantly,

(b) orally administering a dose of tolperisone or a pharmaceutically acceptable salt thereof, which is less (e.g., at least 5% less) than the standard dose that would be administered to a patient who is not concomitantly administered the CYP2D6 inhibitor or the CYP2C19 inhibitor.

[055] In some embodiments, the present disclosure provides a method of concomitantly treating a patient having muscle spasm associated with acute, painful musculoskeletal conditions with i) tolperisone and ii) a cytochrome P450 2D6 (CYP2D6) inhibitor or a cytochrome P450 2C19 (CYP2C19) inhibitor, comprising orally administering to the patient a dose of tolperisone or a pharmaceutically acceptable salt thereof, which is less (e.g., at least 5% less) than the dose that would be administered to a patient not concomitantly administered the CYP2D6 inhibitor or the CYP2C19 inhibitor.

[056] In some embodiments, the CYP2D6 inhibitor or the CYP2C19 inhibitor is administered in a therapeutically effective amount.

[057] In some embodiments, the dose of tolperisone or a pharmaceutically acceptable salt thereof is adjusted in patients concomitantly administered a CYP2D6 inhibitor or the CYP2C19 inhibitor. In some embodiments, the adjusted amount is reduced at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%_>, about 40%, about 45%), about 50%, about 55%, about 60%, or about 65% of the dose of the tolperisone or a pharmaceutically acceptable salt thereof normally given to the patient. In some embodiments, the amount of tolperisone or a pharmaceutically acceptable salt is reduced at least about 5%, about 10%, about 15%, about 20%, about 25%„ about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60% of the normal administration and the daily administration of the tolperisone or a pharmaceutically acceptable salt thereof is between about 150 mg and about 600 mg, including about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg and all values and ranges therebetween. In some embodiments, the amount of toiperisone or a pharmaceutically acceptable salt is reduced at least about 20% of the normal administration and the daily administration of the toiperisone or a pharmaceutical iy acceptable salt thereof is between about 150 mg and about 400 mg.

[058] In some embodiments, the adjusted amount is reduced between the range of about 1% to about 65%, about 1% to about 60%, about 1% to about 55%, about 1% to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to 5%, about 5% to about 65%, about 5% to about 60%, about 5% to about 55%, about 5% to 50%. about 5% to about 45%, about 5% to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 25°%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 65%, about 10% to about 60%, about 10% to about 55%, about 10% to about 50%, about 10% to about 45%, about 10% to about 40%, about 10% to about 35%, about 10% to about 30%, about 10% to about 25%, about 10% to about 20%, about 10% to about 15%, about 15% to about 65%, about 15% to about 60%, about 15% to about 55%, about 15% to about 50%, about 15% to about 45%, about 15% to about 40%, about 15% to about 35%, about 15% to about 30%, about 15% to about 25%, about 15% to about 20%, about 15% to about 15%, about 15% to about 10%, about 20% to about 65%, about 20% to about 60%, about 20% to about 55%, about 20% to about 50%, about 20% to about 45%, about 20% to about 40%, about 20% to about 35%, about 20% to about 30%, about 20% to about 25%, about 25% to about 65%, about 25% to about 60%, about 25% to about 55%, about 25% to about 50%, about 25% to about 45%, about 25% to about 40%, about 25% to about 35%, about 25% to about 30%, about 30% to about 65%, about 30% to about 60%, about 30% to about 55%, about 30% to about 50%, about 30% to about 45%, about 30% to about 40%, about 30% to 35%, about 35% to about 65%, about 35% to about 60%, about 35% to about 55%, about 35% to about 50%, about 35% to about 45%, about 35% to about 40%, about 40% to about 50%, relative to the dose of the toiperisone or a pharmaceutically acceptable salt normally given to the patient. [059] In some embodiments, the dose of tolperisone or pharmaceutically acceptable salt thereof without concomitant administration of the CYP2D6 inhibitor or the CYP2C19 inhibitor is from about 150 mg to 600 mg, including about 200 mg, about 250 rag, about 300 mg, about 350 mg, about •400 mg, about 450 mg, about 500 mg, and about 550 mg (including all values and ranges therebetween) per day. In some embodiments, the dose of tolperisone or pharmaceutically acceptable salt thereof without concomitant administration of the CYP2D6 inhibitor or the CYP2C19 inhibitor is from about 450 mg to 600 mg per day.

[060] In some embodiments, the dose of tolperisone or pharmaceutically acceptable salt thereof without concomitant administration of the CYP2D6 inhibitor or the CYP2C19 inhibitor is about 150 about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg and about 600 mg day. In some embodiments, the dose of tolperisone or pharmaceutically acceptable salt thereof without concomitant administration of the CYP2D6 inhibitor or the CYP2C19 inhibitor is about 450 mg per day.

[061] In some embodiments, the patient is receiving a concomitant administration of a CYP2D6 inhibitor. In some embodiments, the cytochrome P450 2D6 inhibitor is selected from the group consisting of amiodarone, bupropion, chloroquine, cimetidine, cinacalcet, diphenhydramine, doxorubicin, fluoxetine, haloperidol, imatinib, metoclopramide, methadone, paroxetine, propafenone, propoxyphene, quinidine, ritonavir, terbinafme and thioridazine. In some embodiments, the CYP2D6 inhibitor is selected from the group consisting of cimetidine, cocaine, doxorubicin, metoclopramide, methadone, paroxetine, quinidine, ritonavir, and terbinafme. In some embodiments, the cytochrome P4502D6 inhibitor is paroxetine.

[062] In some embodiments, the patient is receiving a concomitant administration of a CYP2C19 inhibitor. In some embodiments, the CYP2C19 inhibitor is selected from the group consisting of chloramphenicol, cimetidine, clopidogrel, delavirdine, efavirenz, esomeprazole, felbamate, fluconazole, fluoxetine, fluvoxamine, isoniazid, moclobemide, modafmil, omeprazole, oxcarbazepine, ticlopidine, and voriconazole. In some embodiments, the CYP2C19 inhibitor is selected from the group consisting of omeprazole, fluvoxamine, and moclobemide. In some embodiments, the cytochrome P4502C19 inhibitor is fluvoxamine. [063] In one aspect, the present disclosure provides a method of safely administering tolperisone or a pharmaceutically acceptable salt thereof for the treatment of muscle spasm or spastic syndrome in a patient who is being administered tolperisone or a pharmaceutically acceptable salt thereof, the method comprising: (1) determining if the patient has taken or will take, a concomitant dose of a CYP2D6 inhibitor or a cytochrome CYP2C19 inhibitor and (2) orally administering to the patient at least a 5% decrease in an effective dosage amount of tolperisone or a pharmaceutically acceptable salt thereof when the patient is receiving a concomitant administration of a CYP2D6 inhibitor or a CYP2C19 inhibitor.

[064] In some embodiments, the amount of tolperisone or salt thereof is reduced at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, or about 65%. In some embodiments, the amount of tolperisone or salt thereof is reduced at least about 20%. In some embodiments, the amount of tolperisone or salt thereof is reduced at least about 50%.

[065] In some embodiments, the method further comprises recommending to decrease the dose of tolperisone or salt thereof to about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, or about 550 mg per day. In some embodiments, the method further comprises recommending to decrease the dose of tolperisone or salt thereof to about 300 mg per day.

[066] In some embodiments, the recommended daily dose comprises administering about 50 mg, about 100 mg, or about 150 mg of tolperisone or a pharmaceutically acceptable salt thereof three time daily (“t.i.d ”). In some embodiments, the recommended daily dose comprises administering about 100 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d.

[067] In some embodiments, the present disclosure provides, a method for treating a patient with muscle spasm or spastic syndrome, the method comprising: (1) administering a therapeutically effective amount of a composition comprising a daily dose of about 450 mg to 600 mg tolperisone or a pharmaceutically acceptable salt there; (2) determining if the patient is being administered a CYP2D6 inhibitor or a cytochrome CYP2C19; (3) warning of a potential drug/drug interaction due to the combination of the CYP2D6 inhibitor or a cytochrome CYP2C19 and tolperisone; and (4) recommending reducing the dose of tolperisone by at least about 5%. [068] In some embodiments, the recommended reduction in the amount of tolperisone or pharmaceutically acceptable salt thereof is at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, or about 65%. In some embodiments, the recommended reduction in the amount of tolperisone or salt thereof is at least about 20%.

[069] In some embodiments, the CYP2D6 inhibitor or a CYP2C19 inhibitor is administered within about one week, about two weeks, about three weeks or about four weeks of administration of tolperisone or a pharmaceutically acceptable salt thereof. In some embodiments, the CYP2D6 inhibitor or a CYP2C19 inhibitor is administered within about two weeks of administration of tolperisone or a pharmaceutically acceptable salt thereof.

[070] In some embodiments, the CYP2D6 inhibitor or a CYP2C19 inhibitor is administered within about one day, about two days, about three days, about four days, about five days, about six days or about seven days of administration of tolperisone or a pharmaceutically acceptable salt thereof. In some embodiments, the CYP2D6 inhibitor or a CYP2C19 inhibitor is administered within about three days of administration of tolperisone or a pharmaceutically acceptable salt thereof.

[071] In some embodiments, the CYP2D6 inhibitor or a CYP2C19 inhibitor is administered within about 1 h, about 2 h, about 3 h, about 4 h, about 5 h, about 6 h, about 7 h, about 8 h, about 9 h, about 10 h, about 11 h, about 12 h, about 13 h, about 14 h, about 15 h, about 16 h, about 17 h, about 18 h, about 19 h, about 20 h, about 21 h, about 22 h, about 23 h, or about 24 h of administration of tolperisone or a pharmaceutically acceptable salt thereof.

[072] In some embodiments, CYP2D6 inhibitor or a CYP2C19 inhibitor is co-administered with the tolperisone or a pharmaceutically acceptable salt thereof.

[073] In some embodiments, the dosages are divided over the course of a day, e.g. a recommended daily dose divided into five doses, or four doses, or three doses, or two doses.

[074] Additionally, the dosage of a tolperisone composition administered to a subject can be limited to prevent overexposure of the subject to 4-MMPPO. Therefore, in another particular embodiment, the total daily dose results in a daily exposure to the patient of less than about 20 pg, preferably less than about 10 pg, and more preferably less than about 1.5 pg of 4-MMPPO. [075] Depending upon the dosage amount and precise condition to be treated, administration can be over a time course of one day to several days, weeks, months, or longer. Illustrative dosing regimens will last a period of at least about a day, a week, from about 1-4 weeks, from 1-3 months, from 1-6 months, from 1-50 weeks, from 1-12 months, or longer.

[076] In some embodiments, the tolperisone is administered for a period of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 24 weeks or about 50 weeks.

[077] In some embodiments, the tolperisone is administered one time per day, two times per day, three times per day or four times per day, and particularly three times per day.

[078] Furthermore, it has been discovered that in certain patients, a tolperisone dose adjustment is not necessary to safely concomitantly administer tolperisone (or a pharmaceutically acceptable salt thereof) and a CYP2D6 or a CYP2C19. In some embodiments, the present disclosure provides a method of treating muscle spasm associated with acute, painful musculoskeletal conditions in a patient in need thereof with tolperisone or a pharmaceutically acceptable salt thereof, the method comprising: orally administering to a patient receiving concomitant administration of a cytochrome P4502D6 (CYP2D6) inhibitor or a cytochrome P4502C19 (CYP2C19) inhibitor the same effective dosage amount of tolperisone or salt thereof received by a patient not receiving concomitant administration of a cytochrome P450 2D6 (CYP2D6) inhibitor or a cytochrome P450 2C19 (CYP2C19) inhibitor (i.e., no tolperisone dose adjustment is required). In some embodiments, the dose of tolperisone or pharmaceutically acceptable salt thereof with concomitant administration of the CYP2D6 inhibitor or the CYP2C19 inhibitor is from about 150 mg to about 600 mg per day, including about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 70 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, and about 600 mg, including all ranges therebetween. TOLPERISONE DOSES IN CYP2D6 POOR METABOLIZERS

[079] In one aspect, the present disclosure relates to the surprising discovery that treatment of a patient, who has lower CYP2D6 activity than a normal person, with tolperisone or a pharmaceutically acceptable salt thereof can he accomplished safely and efficaciously by administering the same dose of the drug that would be administered to a person who has normal CYP2D6 enzyme activity.

[080] Patients who have lower than normal CYP2D6 activity are herein referred to as CYP2D6 Poor Metabolizers. An analysis of Phase 2 study results led to the unexpected discovery that patients in this population receiving the same dose as a normal person did not suffer from a higher incidence of adverse events, despite the increased tolperisone exposure. Consequently, in some embodiments, no adjustment in the close of tolperisone or a pharmaceutically acceptable salt thereof is necessary in patients that have lower CYP2D6 activity than a normal CYP2D6 metabolizer.

[081] The cytochrome P450 2D6 gene (CYP2D6) is located on chromosome 22 and encodes a Phase I drug metabolizing enzyme that is implicated in the metabolism of many drugs, including tolperisone. The CYP2D6 gene is highly polymorphic. The two most common polymorphisms within the CYP2D6 gene in Caucasian populations are CYP2D6G1846A and CYP2D6P34S (also referred to as CYP2D6C100T) (Bradford L D. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 2002 March; 3(2):229-43).

[082] The CYP2D6G1846A polymorphism (also referred to herein as “CYP2D6*4” alleles, include *4A, *4B, *4C, *4D, *4E, *4F, *4G, *4H, *4J, *4K, and *4L) represents a G to A transition at the junction between intron 3 and exon 4, shifting the splice junction by one base pair, resulting in frameshift and premature termination of the protein. The CYP2D6P34S/CYP2D6C100T polymorphism (also referred to herein as “CYP2D6*10” and “CYP2D6*14” alleles) represents a C to T change that results in the substitution of a Proline at position 34 by Serine. Both of CYP2D6*4 and CYP2D6* 10 polymorphisms have been associated with reduced enzymatic activity for different substrates (see, e.g., Bertilsson L, et ah, Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 2002 February; 53(2): 111-22).

[083] In some embodiments, the present disclosure provides a method of treating muscle spasm associated with acute, painful musculoskeletal conditions in a patient in need thereof who is a CYP2D6 poor metabolizer, comprising: orally administering to the patient a daily dose of tolperisone or salt that is the same daily dose as a patient who does not have a CYP2D6 poor metabolizer genotype.

[084] In some embodiments, the administered daily dose of tolperisone or a pharmaceutically acceptable salt thereof is from about 450 mg to 600 mg per day.

[085] In some embodiments, the administration to the patient having a CYP2D6 poor metabolizer genotype provides about the same incidence of adverse events related to treatment with tolperisone as observed in patients not having a CYP2D6 poor metabolizer genotype who are administered the same tolperisone dose.

[086] In some embodiments, the administration to the patient having a CYP2D6 poor metabolizer genotype does not increase the incidence of somnolence compared to the incidence of somnolence patients not having a CYP2D6 poor metabolizer genotype who are administered the same tolperisone dose.

[087] In some embodiments, the CYP2D6 poor metabolizer genotype is selected from the group consisting of CYP2D6*4, *9, *10, *17, *29 and *41. In some embodiments, the CYP2D6 poor metabolizer genotype is CYP2D6*4. In some embodiments, the CYP2D6 poor metabolizer genotype is CYP2D6*10.

[088] In some embodiments, the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day comprises administering about 600 mg of tolperisone or a pharmaceutically acceptable salt thereof. In some embodiments, the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day comprises administering about 450 mg of tolperisone or a pharmaceutically acceptable salt thereof. In some embodiments, the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day comprises administering about 200 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d. In some embodiments, the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day comprises administering about 150 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d.

[089] Methods of determining whether a patient is a CYP2D6 Poor Metaboiizers are described in U.S. Patent No. 8,586,610, which is hereby incorporated by reference in its entirety for all purposes.

[090] In another aspect, the present disclosure relates to treatment of some patients, who have lower CYP2D6 activity than a normal person, with tolperisone or a pharmaceutically acceptable salt thereof and that i s metabolized in part by the CYP2D6 enzyme, and can be accomplished more safely and/or efficaciously by administering a lower dose of the drug than would be administered to a person who has normal CYP2D6 enzyme activity.

[091] In some embodiments, the present disclosure provides a method of safely administering tolperisone or a pharmaceutically acceptable salt thereof for the treatment of muscle spasm or spastic syndrome, the method comprising: (1) determining whether the patient is a CYP2D6 poor metabolizer by determining if the patient has a CYP2D6 poor metabolizer genotype; (2) if the patient has CYP2D6 poor metabolizer genotype, then orally administer a daily dose of tolperisone or salt from about 150 mg to 400 mg per day; and (3) if the patient does not have a CYP2D6 poor metabolizer genotype, then orally administer a daily dose of tolperisone or salt from about 450 mg to 600 mg per day.

[092] In some embodiments, the CYP2D6 poor metabolizer genotype is selected from the group consisting of CYP2D6*4, *9, *10, *17, *29 and *41. In some embodiments, the CYP2D6 poor metabolizer genotype is CYP2D6*4. In some embodiments, the CYP2D6 poor metabolizer genotype is CYP2D6*10.

[093] In some embodiments, the step of administering a daily dose of tolperisone or salt from about 150 mg to 400 mg per day comprises administering about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350, or about 400 mg of tolperisone or a pharmaceutically acceptable salt thereof. In some embodiments, the step of administering a daily dose of tolperisone or salt from about 150 mg to 400 mg per day comprises administering about 400 mg of tolperisone or a pharmaceutically acceptable salt thereof. In some embodiments, the step of administering a daily dose of tolperisone or salt from about 150 mg to about 400 mg per day comprises administering about 300 mg of tolperisone or a pharmaceutically acceptable salt thereof.

[094] In some embodiments, the step of administering a daily dose of tolperisone or salt from about 150 mg to about 400 mg per day comprises administering about 50 mg, about 100 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d. In some embodiments, the step of administering a daily dose of tolperisone or salt from about 150 mg to 400 mg per day comprises administering about 100 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d.

TOLPERISONE FORMULATIONS

[095] In addition to comprising tolperisone, a formulation of the invention may optionally contain one or more additional components.

[096] A composition of the invention may comprise, in addition to tolperisone, one or more pharmaceutically acceptable excipients or carriers. Exemplary excipients include, without limitation, polyethylene glycol (PEG), hydrogenated castor oil (HCO), cremophors (polyethoxylated castor oil), carbohydrates, starches (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders/fillers, surfactants, lubricants (e.g., calcium or magnesium stearate), glidants such as talc, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), diluents, buffers, acids, bases, film coats, combinations thereof, and the like.

[097] A composition of the invention may include one or more carbohydrates such as a sugar, a derivatized sugar such as an alditol, aldonic acid, an esterified sugar, and/or a sugar polymer. Specific carbohydrate excipients include, for example: monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffmose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like.

[098] Also suitable for use in the compositions of the invention are potato and corn-based starches such as sodium starch glycolate and directly compressible modified starch. [099] Further representative excipients include inorganic salts or buffers such as citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.

[0100] A tolperisone composition may also include an antimicrobial agent, e.g., for preventing or deterring microbial growth. Non-limiting examples of antimicrobial agents suitable for the present invention include benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, thimersol, and combinations thereof.

[0101] A composition as provided herein may also contain one or more antioxidants. Antioxidants are used to prevent oxidation, thereby preventing the deterioration of the tolperisone or other components of the preparation. Suitable antioxidants for use in the present invention include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabi sulfite, and combinations thereof.

[0102] Additional excipients include surfactants such as polysorbates, e.g., "Tween 20" and "Tween 80," and pluronics such as F68 and F88 (both of which are available from BASF, Mount Olive, New Jersey), sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, and phosphatidylethanolamines), fatty acids and fatty esters, steroids such as cholesterol, and chelating agents, such as EDTA, zinc and other such suitable cations.

[0103] Further, as described previously, a composition of the invention may optionally include one or more acids. Non-limiting examples of acids that can be used include those acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, succinic acid, adipic acid, propionic acid, toluenesulfonic acid, methanesulfonic acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof.

[0104] In one embodiment, a composition provided herein comprises tolperisone hydrochloride, citric acid anhydrous, lactose anhydrous, stearic acid, starch pregelatinized, crospovidone, polyethylene glycol 6000, hypromellose, lactose monohydrate, titanium dioxide, macrogol PEG. [0105] In a preferred embodiment, a composition as provided herein is absent a basic component.

[0106] The amount of any individual excipient in the composition will vary depending on the role of the excipient, the dosage requirements of the active agent (i.e., tolperisone), and particular needs of the composition. Typically, the optimal amount of any individual excipient is determined through routine experimentation, i.e., by preparing compositions containing varying amounts of the excipient (ranging from low to high), examining the stability and other parameters, and then determining the range at which optimal performance is attained with no significant adverse effects.

[0107] Generally, however, the excipient will be present in the composition in an amount of about 1% to about 99% by weight, preferably from about 5% to about 98% by weight, more preferably from about 15 to about 95% by weight of the excipient. In general, the amount of excipient present in a tolperisone composition of the invention is selected from the following: at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 95% by weight.

[0108] Exemplary formulations for administration include those currently on the market, e.g., Mydeton®, Mydocalm®, Midocalm® and Muscalm®, and similar such formulations.

[0109] Tolperisone may be provided in a sustained-release formulation. See, e.g., Example 7, and International Patent Publication No. WO 2005/094825. Controlled or sustained-release formulations are typically prepared by incorporating tolperisone into a carrier or vehicle such as liposomes, nonresorbable impermeable polymers such as ethylenevinyl acetate copolymers and Hytrel® copolymers, swellable polymers such as hydrogels, or resorbable polymers such as collagen and certain polyacids or polyesters such as those used to make resorbable sutures.

[0110] One exemplary controlled release formulation includes a mixture of anionic and cationic polymers, such as Eudragit RS, Eudragit L and Eudragit S. Additionally, tolperisone can be encapsulated, adsorbed to, or associated with, particulate carriers. Examples of particulate carriers include those derived from polymethyl methacrylate polymers, as well as microparticles derived from poly(lactides) and poly(lactide-co-glycolides), known as PLG. See, e.g., Jeffery et ah, Pharm. Res. (1993) 10:362-368; and McGee et ah, J. Microencap. (1996). Tablets or caplets may also be coated with water insoluble polymers, e.g, Aquacoat® and Eudragit®. [0111] The foregoing pharmaceutical excipients along with other excipients are described in "Remington: The Science & Practice of Pharmacy", 19th ed., Williams & Williams, (1995), the "Physician's Desk Reference", 52nd ed., Medical Economics, Montvale, NJ (1998), and Kibbe, A.H., Handbook of Pharmaceutical Excipients, 3rd Edition, American Pharmaceutical Association, Washington, D.C., 2000.

TOLPERISONE DOSAGE FORMS

[0112] The tolperisone described herein may be formulated into any form suitable for administration. Oral dosage forms include tablets, lozenges, capsules, syrups, oral suspensions, emulsions, granules, and pellets. Alternative formulations include aerosols, transdermal patches, gels, creams, ointments, suppositories, powders or lyophilates that can be reconstituted, as well as liquids. With respect to liquid pharmaceutical compositions, solutions and suspensions are envisioned. Preferably, tolperisone is provided in a form suitable for oral administration.

[0113] For example, tablets can be made by compression or molding, optionally with one or more accessory ingredients or additives. Compressed tablets are prepared, for example, by compressing in a suitable tabletting machine, the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) and/or surface-active or dispersing agent.

[0114] Molded tablets are made, for example, by molding in a suitable tabletting machine, a mixture of powdered compounds moistened with an inert liquid diluent. The tablets may optionally be coated or scored, and may be formulated so as to provide slow or controlled release of the active ingredients, using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, such as a thin film, sugar coating, or an enteric coating to provide release in parts of the gut other than the stomach. Processes, equipment, and toll manufacturers for tablet and capsule making are well-known in the art.

[0115] The compositions of the present invention may also be prepared in a form suitable for veterinary applications. TOLPERISONE ADMINISTRATION

[0116] Methods of administering therapeutic formulations of tolperisone include, but are not limited to, oral, parenteral (including intra-arterial, intraspinal, intramuscular, intraperitoneal, intravenous, subcutaneous, intramuscular, and intradermal), rectal, nasal, topical (including transdermal, aerosol, buccal and sublingual), vaginal, intrathecal, and inhalation routes. The preferred route will vary with the condition and age of the recipient, the particular condition treated, and if tolperisone is used in combination with an analgesic, the specific combination of drugs employed.

[0117] Preferred routes of administration are intramuscular, intravenous, and oral. In a particularly preferred embodiment, tolperisone is administered orally.

EMBODIMENTS

1. A method of treating muscle spasm associated with acute, painful musculoskeletal conditions in a patient in need thereof with tolperisone or a pharmaceutically acceptable salt thereof, the method comprising: orally administering to the patient at least a 5% decrease in an effective dosage amount of tolperisone or a pharmaceutically acceptable salt thereof when the patient is receiving a concomitant administration of a cytochrome P450 2D6 (CYP2D6) inhibitor or a cytochrome P450 2C19 (CYP2C19) inhibitor.

2. The method of embodiment 1, wherein there is an at least at a 20% decrease in an effective dosage amount of tolperisone or a pharmaceutically acceptable salt thereof when the patient is receiving a concomitant administration of a CYP2D6 inhibitor or CYP2C19 inhibitor.

3. The method of embodiment 2, wherein the effective dosage amount is a reduction of about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45% or about 45% to 50% of the tolperisone the normally administered to the patient.

4. The method of any one of embodiments 1-3, wherein the dose of tolperisone or a pharmaceutically acceptable salt thereof without concomitant administration of the CYP2D6 inhibitor or the CYP2C19 inhibitor is from about 450 mg to 600 mg per day. 5. The method of any one of embodiments 1-4, wherein the effective dose of tolperisone or a pharmaceutically acceptable salt thereof is from about 150 mg to 400 mg per day.

6. The method any one of embodiments 1-5, wherein the patient is receiving a concomitant administration of a CYP2D6 inhibitor.

7. The method of embodiment 6, wherein the cytochrome P4502D6 inhibitor is selected from the group consisting of amiodarone, bupropion, chloroquine, cimetidine, cinacalcet, diphenhydramine, doxorubicin, fluoxetine, haloperidol, imatinib, metoclopramide, methadone, paroxetine, propafenone, propoxyphene, quinidine, ritonavir, terbinafme and thioridazine.

8. The method of embodiment 7, wherein the cytochrome P4502D6 inhibitor is paroxetine.

9. The method any one of embodiments 1-5, wherein the patient is receiving a concomitant administration of a CYP2C19 inhibitor.

10. The method of embodiment 9, wherein the CYP2C19 inhibitor is selected from the group consisting of chloramphenicol, cimetidine, clopidogrel, delavirdine, efavirenz, esomeprazole, felbamate, fluconazole, fluoxetine, fluvoxamine, isoniazid, moclobemide, modafmil, omeprazole, oxcarbazepine, ticlopidine, and voriconazole.

11. The method of embodiment 10, wherein the cytochrome P4502C19 inhibitor is fluvoxamine.

12 A method of safely administering tolperisone or a pharmaceutically acceptable salt thereof for the treatment of muscle spasm associated with acute, painful musculoskeletal conditions in a patient who is being administered tolperisone, the method comprising: determining if the patient has taken or will take, a concomitant dose of a CYP2D6 inhibitor or a cytochrome CYP2C19 inhibitor and orally administering to the patient at least a 5% decrease in an effective dosage amount of tolperisone or a pharmaceutically acceptable salt thereof when the patient is receiving a concomitant administration of a CYP2D6 inhibitor or a CYP2C19 inhibitor.

13. The method of embodiment 12, wherein the amount of tolperisone or a pharmaceutically acceptable salt thereof is reduced at least 20%. 14. The method of embodiment 12, wherein the CYP2D6 inhibitor or a CYP2C19 inhibitor is administered within two weeks of administration of tolperisone or a pharmaceutically acceptable salt thereof.

15. The method of embodiment 12, wherein the CYP2D6 inhibitor or a CYP2C19 inhibitor is administered within three days of administration of tolperisone or a pharmaceutically acceptable salt thereof.

16. The method of embodiment 12, further comprising recommending to decrease the dose of tolperisone or a pharmaceutically acceptable salt thereof to about 300 mg per day.

17. The method of embodiment 16, wherein the recommended daily dose comprises administering about 100 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d.

18. A method for treating a patient with muscle spasm associated with acute, painful musculoskeletal conditions, the method comprising: administering a therapeutically effective amount of a composition comprising a daily dose of about 450 mg to 600 mg tolperisone or a pharmaceutically acceptable salt thereof; determining if the patient is being administered a CYP2D6 inhibitor or a CYP2C19 inhibitor; warning of a potential drug/drug interaction due to the combination of the CYP2D6 inhibitor or a cytochrome CYP2C19 inhibitor and tolperisone; and recommending reducing the dose of tolperisone by at about 5%.

19. The method of embodiment 18, wherein the CYP2D6 inhibitor or a CYP2C19 inhibitor is administered within two weeks of administration of tolperisone or a pharmaceutically acceptable salt thereof.

20. The method of embodiment 18, wherein the CYP2D6 inhibitor or a CYP2C19 inhibitor is administered within three days of administration of tolperisone or a pharmaceutically acceptable salt thereof.

21. The method of any of embodiments 1-20, wherein the tolperisone comprises tolperisone hydrochloride.

22. The method of any of embodiments 1-20, wherein the tolperisone is provided in a composition comprising tolperisone hydrochloride, citric acid anhydrous, lactose anhydrous, stearic acid, starch pregelatinized, crospovidone, polyethylene glycol 6000, hypromellose, lactose monohydrate, titanium dioxide, and macrogol PEG.

23. A method of safely administering tolperisone or a pharmaceutically acceptable salt thereof for the treatment of muscle spasm associated with acute, painful musculoskeletal conditions, the method comprising: determining whether the patient is a CYP2D6 poor metabolizer by determining if the patient has a CYP2D6 poor metabolizer genotype; if the patient has a CYP2D6 poor metabolizer genotype, then orally administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof that is the same daily dose as a patient who does not have a CYP2D6 poor metabolizer genotype.

24. The method of embodiment 23, wherein the administered daily dose of tolperisone or a pharmaceutically acceptable salt thereof is from about 450 mg to 600 mg per day.

25. The method of any one of embodiments 23-24, wherein the administration to the patient having a CYP2D6 poor metabolizer genotype provides about the same incidence of adverse events related to treatment with tolperisone as observed in patients not having a CYP2D6 poor metabolizer genotype who are administered the same tolperisone dose.

26. The method of any one of embodiments 23-25, wherein the administration to the patient having a CYP2D6 poor metabolizer genotype does not increase the incidence of somnolence compared to the incidence of somnolence patients not having a CYP2D6 poor metabolizer genotype who are administered the same tolperisone dose

27. The method of any one of embodiments 23-26, wherein the CYP2D6 poor metabolizer genotype is selected from the group consisting of CYP2D6*4, *9, *10, *17, *29 and *41.

28. The method of embodiment 27, wherein the CYP2D6 poor metabolizer genotype is CYP2D6*4.

29. The method of embodiment 27, wherein the CYP2D6 poor metabolizer genotype is CYP2D6*10. 30. The method of embodiment 24, wherein the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day comprises administering about 600 mg of tolperisone or a pharmaceutically acceptable salt thereof.

31. The method of embodiment 24, wherein the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day comprises administering about 450 mg of tolperisone or a pharmaceutically acceptable salt thereof.

32. The method of embodiment 24, wherein the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day comprises administering about 200 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d.

33. The method of embodiment 24, wherein the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day comprises administering about 150 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d.

34. A method of treating muscle spasm associated with acute, painful musculoskeletal conditions in a patient in need thereof with tolperisone or a pharmaceutically acceptable salt thereof, the method comprising: orally administering to a patient receiving concomitant administration of a cytochrome P4502D6 (CYP2D6) inhibitor or a cytochrome P4502C19 (CYP2C19) inhibitor the same effective dosage amount of tolperisone or a pharmaceutically acceptable salt thereof received by a patient not receiving concomitant administration of a cytochrome P4502D6 (CYP2D6) inhibitor or a cytochrome P4502C19 (CYP2C19) inhibitor.

35. The method of embodiment 34, wherein the effective dose of tolperisone or a pharmaceutically acceptable salt thereof is from about 450 mg to 600 mg per day.

36. The method of embodiment 35, wherein the step of administering an effective dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day comprises administering about 200 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d. 37. The method of embodiment 34, wherein the step of administering an effective dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day comprises administering about 150 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d.

38. The method of any one of embodiments 34-37, wherein the patient is receiving a concomitant administration of a CYP2D6 inhibitor.

39. The method of embodiment 38, wherein the cytochrome P4502D6 inhibitor is selected from the group consisting of amiodarone, bupropion, chloroquine, cimetidine, cinacalcet, diphenhydramine, doxorubicin, fluoxetine, haloperidol, imatinib, metoclopramide, methadone, paroxetine, propafenone, propoxyphene, quinidine, ritonavir, terbinafme and thioridazine.

40. The method of embodiment 39, wherein the cytochrome P4502D6 inhibitor is paroxetine.

41. The method of any one of embodiments 34-37, wherein the patient is receiving a concomitant administration of a CYP2C19 inhibitor.

42. The method of embodiment 41, wherein the CYP2C19 inhibitor is selected from the group consisting of chloramphenicol, cimetidine, clopidogrel, delavirdine, efavirenz, esomeprazole, felbamate, fluconazole, fluoxetine, fluvoxamine, isoniazid, moclobemide, modafmil, omeprazole, oxcarbazepine, ticlopidine, and voriconazole.

43. The method of embodiment 42, wherein the cytochrome P4502C19 inhibitor is fluvoxamine.

44. The method of any one of embodiments 34-43, wherein orally administering to a patient receiving concomitant administration of an effective dosage amount of tolperisone or a pharmaceutically acceptable salt thereof and a cytochrome P4502D6 (CYP2D6) inhibitor or a cytochrome P4502C19 (CYP2C19) inhibitor provides about the same incidence of adverse events related to treatment observed as a patient receiving the same effective dose of tolperisone or a pharmaceutically acceptable salt thereof not receiving concomitant administration of a cytochrome P4502D6 (CYP2D6) inhibitor or a cytochrome P4502C19 (CYP2C19) inhibitor.

45. A method of safely administering tolperisone or a pharmaceutically acceptable salt thereof for the treatment of muscle spasm associated with acute, painful musculoskeletal conditions, the method comprising: determining whether the patient is a CYP2D6 poor metabolizer by determining if the patient a CYP2D6 poor metabolizer genotype; if the patient has CYP2D6 poor metabolizer genotype, then orally administer a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 150 mg to 400 mg per day; and if the patient does not have a CYP2D6 poor metabolizer genotype, then orally administer a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day.

46. The method of embodiment 45, wherein the CYP2D6 poor metabolizer genotype is selected from the group consisting of CYP2D6*4, *9, *10, *17, *29 and *41.

47. The method of embodiment 46, wherein the CYP2D6 poor metabolizer genotype is CYP2D6*4.

48. The method of embodiment 46, wherein the CYP2D6 poor metabolizer genotype is CYP2D6*10.

49. The method of embodiment 45, wherein the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 150 mg to 400 mg per day comprises administering about 400 mg of tolperisone or a pharmaceutically acceptable salt thereof.

50. The method of embodiment 45, wherein the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 150 mg to 400 mg per day comprises administering about 300 mg of tolperisone or a pharmaceutically acceptable salt thereof.

51. The method of embodiment 45, wherein the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 150 mg to 400 mg per day comprises administering about 100 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d. EXAMPLES

[0118] The following examples illustrate certain aspects and advantages of the present invention, however, the present invention is in no way considered to be limited to the particular embodiments described below.

[0119] The practice of the invention will employ, unless otherwise indicated, techniques of pharmaceutical formulation, separations, pharmacology, and the like, which are within the skill of the art, based upon the guidance provided herein. See, for example, Handbook of Pharmaceutical Manufacturing Formulations, S. K. Niazi (ed.), CRC Press, 2004; Goodman & Gilman, The Pharmacological Basis of Therapeutics, 9th Edition, Hardman, J.G., Gilman, A.G., Limbird, L.E. (eds.), McGraw-Hill, New York, 1995; Basic and Clinical Pharmacology, 18th Edition, Katzung, B. G. (ed.), Appleton & Lange, Norwalk, CN, 2001.

[0120] In the following examples, efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.) but some experimental error and deviation should be accounted for. Each of the following examples is considered to be instructive to one of ordinary skill in the art for carrying out one or more of the embodiments described herein.

EXAMPLE 1: Standard Recrystallization of Tolperisone

[0121] Tolperisone containing 4-MMPPO at levels of greater than 0.5% by weight (referred to hereinafter as 'Crude tolperisone') was employed as the starting material for the recrystallization experiments hereinafter. Crude tolperisone was dissolved in an 85:15 (v/v) mixture of 2-butanone (methyl ethyl ketone) and isopropanol under reflux for 30 minutes. The resulting solution was cooled to 80°C, and the solution was filtered while hot. The filtered solution was then cooled to 5 °C, and stirred for an additional 7 hours. The resulting crystalline precipitate was separated by filtering, followed by washing with methyl ethyl ketone. The recrystallized material was dried in vacuo at 45- 85°C. Based upon HPLC-MS/MS analysis, the recrystallized tolperisone possessed 0.14% by weight 4-MMPPO. EXAMPLE 2: Multiple Stage Recrystallization of Tolperisone

[0122] The approach utilized in Example 1 above was repeated with the exception that multiple stage (repeated) recrystallizations were carried out.

Table 1: 4-MMPPO Content Following Repeated Recrystallizations. Non-Acidified Solvent

[0123] As can be seen from the results in Table 1, multiple recrystallizations from solvents/solvent systems such as methyl ethyl ketone and isopropanol can be effective to provide tolperisone that is substantially absent 4-MMPPO.

EXAMPLE 3 : Recrystallization of Tolperisone Followed by Acid Wash

[0124] Crude tolperisone was dissolved in an 85:15 mixture of 2-butanone (MEK) and isopropanol under reflux for 12 hours. The temperature was decreased to 80 °C and the solution filtered while hot. The filtered solution was cooled to 5 °C and stirred for 7h at 5 °C. The crystalline precipitate was separated by filtering and washed with a 1% hydrochloric aci d/isopropanol mixture, and subsequently dried in vacuo at 45 to 85 °C. Based upon HPLC-MS/MS analysis, a content of 4- MMPPO in the range of 1.5 to 10 ppm was detected in the recrystallized product.

EXAMPLE 4: Recrystallization of Tolperisone Using Acidified Solvent System

[0125] Crude tolperisone was dissolved in an 85:15 (v/v) mixture of 2-butanone (MEK) and isopropanol, accompanied by addition of 1% hydrochloric acid under reflux for 12 hours. The temperature was decreased to 80°C and the solution filtered while hot. The solution was cooled to 5°C and stirred for 7h at 5°C. The crystalline precipitate was separated by filtering, washed with isopropanol, and subsequently dried in vacuo at 45 to 85°C, with lower drying temperatures being preferred. Tolperisone showed enhanced stability during recrystallization in the presence of acid. When 1% (v/v) concentrated aqueous hydrochloric acid was added to the recrystallization mixture, 4-MMPPO levels dropped below 6.6 ppm in the final recrystallized tolperisone product.

EXAMPLE 5: Multiple Recrystallizations of Tolperisone Using Acidified Solvent System

[0126] Crude tolperisone was dissolved in an 85:15 (v/v) mixture of 2-butanone (MEK) and isopropanol, accompanied by addition of 1% hydrochloric acid, under reflux for 12 hours. The temperature was decreased to 80°C and the solution filtered while hot. The solution was cooled to 5°C and stirred for 7h at 5°C. The crystalline precipitate was separated by filtering, washed with isopropanol, and subsequently dried in vacuo at 45 to 85°C, with lower temperatures being preferred. The above recrystallization process was repeated 4 times.

Table 2: _ 4-MMPPO Content Following Repeated Recrystallizations Using Acidified Solvent

[0127] As can be seen from the results in Table 2, the first recrystallization under acidified conditions exhibited the most significant removal of 4-MMPPO and purification of tolperisone.

EXAMPLE 6: Instant Release Caplet Formulation

[0128] A solution of anhydrous citric acid, 2-butanone and isopropyl alcohol is prepared. Tolperisone hydrochloride containing less than 10 ppm 4-MMPPO as described herein is transferred into a granulator, into which the already prepared solution is placed. This mixture is homogenized and subsequently dried in a drier at 60°C, or more preferably, at 40°C. The formed granulate is sifted through a 1.8 mm screen. Silicon dioxide and talcum are added and likewise mixed. Subsequently, the mixture is further mixed with magnesium stearate. Tablets having a diameter of 8 mm and a weight of 155.8-172.2g are produced. The finished granulate is coated with a suspension of hypromellose/hypromellose phthalate in ethanol/water, dyes and additives in a coating tank at a temperature of 55-60°C. The coated tablets are subsequently dried at room temperature. EXAMPLE 7 : Controlled Release Formulation

[0129] Tolperisone containing less than 10 ppm 4-MMPPO as described herein is granulated as the hydrochloride salt in a mixer with a solution consisting of Eudragit RS in butanone with addition of anhydrous citric acid. Subsequently, Eudragit S and Eudragit L are incorporated homogeneously; the mixture is dried and sifted. To the sifted granulate are added tabletting auxiliary agents, and the granulate is tabletted. Tablets having a diameter of 8 mm and a weight of 190 mg are pressed. Subsequently, the tablets are coated ("filmed") with a film material consisting of Eudragit L, dyes, and miscellaneous auxiliary agents, which are dissolved in butanol.

[0130] An example of a controlled release tablet is in Table 3a below, and an example of a coated immediate release tablet is in Table 3b below:

EXAMPLE 8: Concomitant administration of tolperisone and CYP2D6 and CYP2C19 inhibitors

[0131] This clinical study was a phase 1, randomized, 2-period study, single center PK study to assess the effect of CYP2D6 and CYP2C19 inhibitors (paroxetine and fluvoxamine, respectively) on a single oral dose of tolperisone hydrochloride (300mg) in healthy volunteers. Thirty (30) subjects were to be enrolled. Subjects were randomized 1:1 to receive tolperisone hydrochloride and either fluvoxamine or paroxetine. On Day 1, all subjects received a single dose of tolperisone hydrochloride (300 mg). Subjects were discharged from the clinical site approximately 24 hours after Day 1 dosing. Subjects then reported to the clinical site each morning on Days 3 through 6 to receive fluvoxamine (50 mg) or paroxetine (20 mg) dosing. On Day 6, later in the day, subjects reported to the clinical site for admission. On Day 7, subjects received co-administration of tolperisone hydrochloride and either fluvoxamine or paroxetine. Subjects remained in the clinic for approximately 24 hours after the Day 7 dose. Blood samples for PK analysis were collected on Days 1 and 7 before dose administration and at pre-determined times up to 24 hours after dose administration.

[0132] The PK parameters assessed in this study included area under the plasma concentration-time curve (AUC) from 0 hour to the last measurable plasma/serum/blood concentration (AUCo-t), AUC extrapolated to infinity ( AUCo-∞), maximum observed plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and apparent plasma terminal phase half-life (ti/2), in addition to other parameters where deemed appropriate.

Drug:

[0133] Tolperisone hydrochloride (HC1), a centrally acting muscle relaxant, is marketed in Europe and Asia for the treatment of painful reflex muscle spasm and spastic syndromes.

Study Rationale [0134] This study was designed to investigate the effect of CYP2D6 and CYP2C19 inhibitors (i.e., paroxetine and fluvoxamine) on the metabolism of tolperisone hydrochloride.

Participants

[0135] Healthy non-smoking male or female subjects between 18 and 65 years of age, inclusive, who provided written informed consent, met all inclusion/exclusion criteria (below), including body mass index (BMI) requirements, and who agreed to use acceptable means of birth control during the study and until 45 days after study completion/discharge were included in the study. Planned participation for each subject was 9 days (Day 1 to Day 8), which included two 2-night stays in the clinic. Table 4 provides a flow chart indicating the various timed aspects of the study.

Table 4. Study Flow Chart

Inclusion Criteria [0136] Subjects who met the following criteria were eligible for inclusion in the study:

1. Male or female, between 18 and 65 years of age, inclusive;

2. Body mass index (BMI) between 18.5 to 29.9 kg/m². For subjects with a BMI greater than 29.9 kg/m², skin-fold measurements using skin-fold calipers were to be completed to determine body fat percentage. (If the body fat percentage fell within the good to excellent range, the subject could be enrolled.);

3. In good health, determined by no clinically significant findings from medical history, 12- lead ECG, and vital signs;

4. Clinical laboratory evaluations (including chem-20 [fasted at least 8 hours], complete blood count (CBC) [includes hematocrit >35% for women and >38.5% for men], prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR) <1.3, and urinalysis (UA) within the reference range for the test laboratory, unless deemed not clinically significant by the investigator;

5. Negative test for selected drugs of abuse at screening (does not include alcohol) and at check-in (does include alcohol);

6. Negative Hepatitis B surface antigen (HBSag) and human immunodeficiency virus (HIV) antibody screens;

7. Females of child-bearing potential must be surgically sterile, post-menopausal for at least one year, or using an effective method of contraception such as oral or transdermal contraceptives, double-barrier contraception (e.g., spermicidal foam and condoms, diaphragm with spermicide), intrauterine device (IHD), depot progesterone, or implanted contraceptive devices, females of child bearing potential must have a negative serum pregnancy test at screening and Day -1;

8. Males will either be sterile or agree to use from Day -1 until 45 days following study completion/discharge one of the following approved methods of contraception: doublebarrier contraception; a sterile sexual partner; use by female sexual partner contraception such as oral or transdermal contraceptives, double-barrier contraception, IUD, depot progesterone, or implanted contraceptive devices; 9. Able to comprehend and willing to sign an ICF.

[0137] Thirty (30) subjects were enrolled to ensure 24 subjects completed the study. Twenty-nine subjects (29) were included in the PK analysis.

Exclusion Criteria

[0138] The following excluded potential subjects from the study:

1. History or clinical manifestations of significant metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, endocrine, gastrointestinal (including gastric or duodenal ulcers), urological, neurological, psychiatric disorders, or cancer;

2. History of inflammatory arthritis (rheumatoid, lupus, psoriatic arthritis);

3. History of symptomatic hypotension;

4. History of severe physical injury, direct impact trauma, or neurological trauma within 6 months of day -1;

5. History of seizure disorders;

6. History of bipolar or major depressive disorder,

7. History of hypersensitivity or allergies to any drug compound, including lidocaine or non-steroidal anti-inflammatory drugs (NSAIDS);

8. Known intolerance to benzodiazepines;

9. Known intolerance to active and/or inactive ingredients in fluvoxamine or paroxetine;

10. History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs, except that appendectomy, hernia repair, and/or cholecystectomy were allowed;

11. History or presence of an abnormal ECG, which, in the investigator’s opinion, was clinically significant;

12. History of alcoholism, drug abuse, or drug addiction; 13. Use of any nicotine-containing or nicotine-replacement products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 6 months prior to Day -1;

14. Participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within 90 days prior to Day -1;

15. Use of any prescription medications/products (including monoamine oxidase inhibitors, thioridazine, pimozide, or anti-depressants) within 3 months prior to Day -1, with the exception of oral, implantable, or transdermal contraception, unless deemed acceptable by the investigator;

16. Received any vaccination or immunization within 1 month prior to Day -1;

17. Use of any over-the-counter (OTC), non-prescription preparations (including supplements, vitamins, minerals, phytotherapeutic/herbal/plant-derived preparations, the tryptophans, and St. John’s Wort) within 7 days prior to Day -1, unless deemed acceptable by the investigator;

18. Use of alcohol-containing, grapefruit-containing, or caffeine-containing foods or beverages within 72 hours prior to Day -1, unless deemed acceptable by the investigator;

19. Poor peripheral venous access;

20. Donation of blood from 3 months prior to Day -1 or of plasma from 2 weeks prior to screening;

21. Receipt of blood products within 2 months prior to Day -1;

22. Female subjects who were pregnant or nursing;

23. Any acute or chronic condition that, in the opinion of the investigator, would limit the subject’s ability to complete and/or participate in this clinical study.

Outcomes

[0139] The primary objective of this study was to determine the effect of CYP2D6 and CYP2C19 inhibitors (paroxetine and fluvoxamine, respectively) on the single dose PK of tolperisone hydrochloride (300 mg) in healthy subjects. [0140] The secondary objectives of this study were to determine the safety and tolerability of tolperisone hydrochloride (300 mg) in healthy subjects given as a single dose.

Statistical Methods

[0141] Descriptive statistics were performed PK parameters. Where data were available, drug interaction effect was examined between test (tolperisone hydrochloride + paroxetine or fluvoxamine) and reference (tolperisone hydrochloride alone). An analysis of variance was performed, and data for AUC and Cmax were natural log transformed prior to analysis. The 90% confidence intervals (CIs) of the test group mean relative to the reference group mean were obtained by taking the antilog of the corresponding 90% CIs for the difference between the means on the log scale.

Interventions

[0142] Approximately 30 subjects were enrolled and randomized to 1 of 2 dosing groups in a 1:1 ratio (Group 1: Group 2). Healthy male and female subjects were dosed as follows:

• Group 1: Single dose of tolperisone hydrochloride 300 mg followed by a 2-day washout, then 4 days of fluvoxamine (50 mg, once-daily [QD]) alone, then fluvoxamine 50 mg + tolperisone hydrochloride 300 mg on Day 7.

• Group 2: Single dose of tolperisone hydrochloride 300 mg followed by a 2-day washout, then 4 days of paroxetine (20 mg, QD) alone, then paroxetine 20 mg + tolperisone hydrochloride 300 mg on Day 7.

[0143] For this study, single doses of 300 mg of tolperisone hydrochloride were used. Standard doses of paroxetine (20 mg/day) and fluvoxamine (50 mg/day) were used based upon prescribing information for each product respectively.

[0144] On Days 1 and 7, subjects received tolperisone hydrochloride 300 mg (two 150 mg tablets) administered orally with 240 mL of room temperature water at approximately 08:00 hours. A mouth check was performed to verify that the administered dose was swallowed. Doses were preceded by an overnight fast from food (not including water) and were followed by a fast from food (not including water) for at least 4 hours after dose administration. Except as part of dose administration, subjects restricted their consumption of water for 1 hour before dose administration and for 1 hour after dose administration; at all other times during the study, subjects could consume water on an ad libitum basis.

[0145] On Days 3 to 7, fluvoxamine (50 mg tablet) or paroxetine (20 mg tablet) was administered orally with 240 mL of room temperature water at the clinical site by qualified clinical staff at approximately 08:00 hours.

[0146] All subjects received a total of 600 mg tolperisone hydrochloride. In addition, subjects in Group 1 received a total of 250 mg fluvoxamine and subjects in Group 2 received a total of 100 mg paroxetine.

Randomization

[0147] Subj ects were enrolled and randomized to 1 of 2 dosing groups in a 1 : 1 ratio (Group 1 : Group 2). Appropriate unit doses, as described above, were administered to consecutively numbered subjects. Results

[0148] Subject demographics were assessed at Screening. The study population included mostly males (17/30, 56.7%) and was predominantly White (22/30, 73.3%); the mean (SD) age of all subjects was 35 (± 11.9) years. There were no differences between the tolperisone hydrochloride + fluvoxamine and the tolperisone hydrochloride + paroxetine groups in mean weight, height, or body mass index (BMI). A summary of subject demographics is presented in Table 4.

Table 5. Subject Demographics

[0149] The primary objective of this study was to determine the effect of CYP2D6 and CYP2C19 inhibitors (paroxetine and fluvoxamine, respectively) on the single dose PK of tolperisone hydrochloride (300 mg) in healthy subjects.

[0150] A total of 30 subjects were enrolled and treated in the study at a single site. Twenty-nine (96.7%) of the 30 subjects completed the study and each was included in the PK analysis.

[0151] In Group 1, subjects received a single dose of tolperisone hydrochloride (300 mg) followed by a 2-day washout, then 4 days of fluvoxamine (50 mg, once-daily) alone, then fluvoxamine (50 mg) concomitantly with tolperisone hydrochloride (300 mg) on Day 7. In Group 2, subjects received a single dose of tolperisone hydrochloride (300 mg) followed by a 2-day washout, then 4 days of paroxetine (20 mg, once daily) alone, then paroxetine (20 mg) concomitantly with tolperisone hydrochloride (300 mg) on Day 7. Blood samples for pharmacokinetic analysis of tolperisone hydrochloride were collected via direct venipuncture and/or via an indwelling catheter on Days 1 and 7 before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after dosing. Urine samples for PK analysis of tolperisone hydrochloride were collected on Days 1 and 7 during the following time intervals: 0 hour (predose), 0 to 12 hours, and 12 to 24 hours after tolperisone hydrochloride administration. Genotyping for CYP2D6 and CYP2C19 alleles was performed on Day 1.

Pharmacokinetic Analysis

[0152] For each subject, the following PK parameters were calculated, whenever possible, based on the plasma concentrations of tolperisone hydrochloride, according to the model independent approach:

• Cmax - Maximum observed plasma concentration.

• Tmax - Time to maximum plasma concentration.

• AUCo-t - Area under the plasma concentration-time curve from 0 hour to the last measurable plasma/serum/blood concentration, calculated by the linear trapezoidal rule.

• AUCo-∞ - Area under the plasma concentration-time curve extrapolated to infinity, calculated using the formula: AUCo-∞ = AUCo-t + Ct/Ke where Ct is the last measurable plasma concentration and K_e is the apparent terminal phase rate constant.

• ti/2 Apparent plasma terminal phase half-life (whenever possible), where

• ti/2 = (1h2) / l_z.

[0153] In addition, the following PK parameters were calculated, whenever possible, for each subject based on the urine tolperisone hydrochloride concentrations:

• A_e - Amount of drug excreted in the urine over sampling interval.

• CLR - Renal clearance, where CL_R = A_e / AUCo-∞.

Statistical Analysis

[0154] An analysis of variance (ANOVA) was performed on the natural logarithms of Cmax, AUCo- t and AUCo-∞ to examine the effects of fluvoxamine and paroxetine on the pharmacokinetics of tolperisone hydrochloride. The mixed effects linear model procedure (PROC MIXED) of SAS® (version 9.1; SAS Corporation) was used for the analysis of log transformed pharmacokinetic parameters Cmax, AUCo-t and AUCo-∞ with compound symmetry correlation structure to account for the correlation among observations within a subject. The model included fixed effect for study days. The 90% confidence intervals of the test group mean (Day 7) relative to the reference group mean (Day 1) were provided from the analyses. The confidence intervals were used to perform the two one-sided tests procedure for equivalence assessment. These confidence intervals were obtained by exponentiating the endpoints of confidence intervals for the difference of mean logarithms obtained within the framework of the ANOVA model.

[0155] Drug interaction effect were assessed by examining the 90% Cl for the ratio of Day 7 mean (Test) relative to the Day 1 mean (Reference). No drug interaction effect was concluded if the antilog of 90% CIs from the log transformed Cmax, AUCo-t and AUCo-∞ are contained within the interval 80% to 125%. If antilog of the 90% Cl of Cmax, AUCo-t and AUCo-∞ are not contained within the interval 80% to 125%, a drug interaction effect was concluded.

PK Profile Evaluation

[0156] The plasma concentrations on Day 1 before dose administration were all below the limit of quantitation. After single dose administration of tolperisone hydrochloride on study Day 1, the plasma concentrations of tolperisone hydrochloride increased rapidly reaching maximum concentrations within one hour, declining thereafter with a ti/2 of approximately 4 to 5 hours. The plasma concentrations were higher on Day 7 as compared to Day 1 for both treatment groups (Figures 2A and 2B).

[0157] Plasma concentrations of tolperisone hydrochloride increased upon concomitant administration of either fluvoxamine or paroxetine (Table 6).

• Administration of tolperisone hydrochloride on Day 7 concomitantly with fluvoxamine resulted, on average, in about 3 -4-fold increase in both Cmax and AUC with a small increase (23%) in the half-life. The increase was statistically significant for Cmax and AUC (p<0.05).

• Plasma exposure of tolperisone hydrochloride also increased upon concomitant administration with paroxetine. The average Cmax and AUC on Day 7 were about 2-fold higher than Day 1. The increase in both Cmax and AUC was statistically significant (p<0.05). The average half-life was about 12% higher on Day 7 compared to Day 1.

Table 6, PK Parameters of tolperisone hydrochloride Administered Alone (Day 1) or in Combination (Day 7) for Group 1 (Fluvoxamine) and Group 2 (Paroxetine).

[0158] Little tolperisone hydrochloride is excreted unchanged in urine. The average percent of dose excreted unchanged within 24 hours ranged between 0.02% and 0.03% when tolperisone hydrochloride was administered alone. The percent excreted in urine was 4 to 5 fold higher on Day 7 than Day 1. However, the renal clearance remained largely unchanged on Day 7 relative to Day 1. While predose concentrations in urine were below the limit of quantitation in all subjects on Day 1, measurable predose concentrations were observed in Subjects 1 through 13 on Day 7. This is unlikely to be related to carryover from Day 1 dosing especially that the predose plasma concentration were below the limit of quantitation. It is noteworthy that Subjects 1-13 were included in study cohort 1. None of the subjects in cohort 2 had any measurable predose urine concentration.

[0159] . These results suggest that inhibition of CYP2D6 and CYP2C19 by paroxetine and fluvoxamine, respectively, resulted in a significant inhibition of tolperisone hydrochloride metabolism.

Conclusions

[0160] Tolperisone hydrochloride pharmacokinetics were significantly affected by both fluvoxamine and paroxetine suggesting that both CYP2D6 and CYP2C19 mediate the metabolism of tolperisone hydrochloride in vivo. This is consistent with the in vitro metabolism data generated in human liver microsomes. Further, the small amount of tolperisone hydrochloride excreted unchanged in urine (<1%) suggests that tolperisone hydrochloride is extensively metabolized in humans, an observation consistent with the in vitro microsomal stability data.

[0161] The greater inhibition (3 to 4 fold) of the metabolism of tolperisone hydrochloride observed with fluvoxamine (relative to paroxetine) suggests that tolperisone hydrochloride is mainly metabolized by CYP2C19 and to a lesser extent by CYP2D6. However, fluvoxamine is also a potent inhibitor of CYP1A2 and a moderate inhibitor of CYP2C9, CYP3A4 and possibly CYP2D6. Therefore, one cannot exclude the possibility that fluvoxamine inhibited both isozymes (CYP2D6 and CYP2C19) responsible for tolperisone hydrochloride metabolism, and hence the greater inhibition effect of fluvoxamine observed on tolperisone hydrochloride metabolism, as compared to paroxetine.

[0162] In conclusion, concomitant administration of tolperisone hydrochloride with paroxetine and fluvoxamine resulted in a significant (2-4 fold) increase in tolperisone hydrochloride exposure, as measured by Cmax and AUC. This confirms the in vitro metabolism observations that tolperisone hydrochloride is metabolized mainly by CYP2D6 and CYP2C19. Moderate to potent inhibitors of CYP2D6 and CYP2C19 isozymes are likely to result in a significant drug-drug interaction with tolperisone hydrochloride.

EXAMPLE 9: Phase 2 clinical study with tolperisone

[00149] A Phase 2 study with tolperisone is designed as a dose-ranging study to identify the recommended Phase 3 dose to aid in supporting the proposed claim of relief of back pain due to muscle spasm of acute onset. Doses for the Phase 2 study are based on years of historical use of tolperisone for treatment of painful muscle spasms where the therapeutic dose is 300 to 450 mg per day.

[00150] The study is a double-blind, randomized, placebo-controlled, parallel group study of the efficacy and safety of tolperisone or placebo administered as multiple doses three times a day (TID) in approximately 400 male and female subjects experiencing back pain due to or associated with muscle spasm. The tolperisone groups consist of dose levels of 150, 300, 450, and 600 mg administered TID in doses of 50, 100, 150, or 200 mg for 14 days, with a visit at 28 days as followup. Subjects randomized to the placebo group receive matching placebo tablets TID for 14 days with a follow-up visit at Day 28. Subject participation is approximately 4 weeks.

[00151] A sample size of 400 subjects (80 per group) provides at least 80% power to detect a difference of 0.9 between the placebo and treatment groups in the NRS scale, assuming a two-sample t-test at the 5% level of significance and a pooled SD of 2.0. This sample size assumes an effect size of 0.45 (0.9/2.0 = 0.45, using the formula Effect Size = Mean/SD), which is larger than that seen in the reference study but consistent with that seen in a second study. Though the primary comparison of interest in this study is Day 14, the study is sufficiently powered to detect a treatment difference at Day 4 based on effect sizes ranging from 0.35 to 0.45. Though the primary comparison of interest in this study is Day 14, the study is sufficiently powered to detect a treatment difference at Day 4 based on effect sizes ranging from 0.35 to 0.45.

[00152] The primary objective of the study is to assess the efficacy of tolperisone daily doses 150, 300, 450, and 600 mg for relief of pain due to acute back muscle spasm.

[00153] The secondary objectives are: • to assess the safety and tolerability of tolperisone in subjects with pain due to acute back spasm.

• to determine the onset of action of tolperisone in treatment of pain due to acute back spasm.

• to determine the duration of pain relief of tolperisone in treatment of pain due to acute back spasm.

• to determine the need for rescue medication when treated with various doses of tolperisone for pain due to acute back spasm.

Study Rationale

[00154] This Phase 2 study explores the efficacy and safety of tolperisone at doses up to 600 mg administered TID for 14 days in patients with acute and painful back muscle spasms.

Participants

[00155] A total of 415 subj ects were enrolled and analyzed for both safety and efficacy, including 78 subjects in the placebo group and 337 subjects in the total tolperisone group (Table 7). The study was conducted at 37 clinical sites in the USA.

Table 7, Demographic and Baseline Characteristics for Intent-to-Treat Population.

Inclusion Criteria

[00156] Approximately 400 male and female subjects between the ages of 18 and 65 years, with acute back pain and/or stiffness due to acute and painful muscle spasms starting within 7 days prior to study entry and more than 8 weeks after the last episode of acute back pain, who had pain localized below the neck and above the inferior gluteal folds with intensity of 4 or more on the subject “right now” rating of pain intensity.

[00157] Subjects who met the following criteria are eligible for inclusion in the study:

1. Ambulatory male or female, 18 to 65 years of age.

2. Current acute back pain and/or stiffness due to acute and painful muscle spasm starting within 7 days prior to study entry and more than 8 weeks after the last episode of acute back pain.

3. Subjects must have pain of 4 or more on the subject “right now” rating of pain intensity NRS scale of 0 - 10 points at baseline.

4. Must be willing to discontinue all medication used for the treatment of pain or muscle spasm on study entry at Day 1 including but not restricted to: a. Ibuprofen (Motrin) b. Diclofenac (Voltaren) c. Celocoxib (Celebrex) d. Naproxen (Aleve) e. Tolmetin (Tolectin) f. Cyclobenzaprine (Flexeril) g. Cyclobenzaprine (Amrix) h. Metaxolone (Skelaxin) i. Methocarbamol (Robaxin) j. Other nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., aspirin) k. Carisoprodol (Soma) l. Tizanidine (Zanaflex, Sirdalud)

5. Pain localized below the neck and above the inferior gluteal folds.

6. Body mass index ranging between 18 and 35 kg/m2.

7. All subjects must be capable of understanding and complying with the protocol and have signed the informed consent document.

8. Female subjects must have a negative urine pregnancy test at screening, must be postmenopausal (amenorrhea for at least 2 years), surgically sterile, or practicing or agree to practice an effective method of birth control if they are sexually active before study entry, during the study, and 2 weeks after the end of the study by using an acceptable method of contraception. Acceptable methods of birth control must be used for at least 14 days prior to the use of study drug. Acceptable methods of birth control include oral, injectable, subdermal implant, vaginal or patch contraceptives, intrauterine device (IUD; copper or hormonal IUD), or double-barrier method (e.g., condom, diaphragm or cervical cap with spermicidal foam, cream, gel, or suppository).

9. Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Thirty (30) subjects were enrolled to ensure 24 subjects completed the study. Twenty-nine subjects (29) were included in the PK analysis.

Exclusion Criteria

[00158] The following excluded potential subjects from the study:

1. Unwillingness to stop taking pain or antispasmodic medication other than the study medication (specifically opioid use [e.g., Vicodin], barbiturates, and cannabis).

2. Chronic back pain for the previous 3 months or longer, on more days than not.

3. Radicular pain in the lower extremity (i.e. pain radiating below the knee), sciatica pain down the leg, or pain below the knee (indicating a lumber radiculopathy); radicular pain in the upper extremity, radiating into the forearm or hand (indicating a cervical radiculopathy). 4. Concomitant severe pain in a region other than the back.

5. Spinal surgery within 1 year of study entry. 6. Back pain due to major trauma (e.g., motor vehicle accident, fracture of bone) unless resolved for more than 1 year.

7. Treatment of back pain ongoing with non-pharmacological therapy (e.g. acupuncture, chiropractic adjustment, massage, Transcutaneous Electrical Nerve Stimulation [TENS], physiotherapy).

8. Female subjects who are pregnant or lactating.

9. Subjects who are taking Baclofen (Lioresal, Liofen, Gablofen, etc.) or Botox (onabotulinumtoxin A) for pain.

10. Subjects who test positive for alcohol by breathalyzer test.

11. Known history or symptoms suspicious of: a. Spinal fracture within previous 3 years b. Osteoporosis with fracture c. Cancer except cutaneous cancers (e.g., melanoma, squamous cell carcinoma) d. Constitutional symptoms such as recent unexplained chills or weight loss e. Spinal infection f. Intravenous drug abuse g. Immunosuppression h. Cauda equina syndrome i. History of chronic severe scoliosis (childhood).

12. Myasthenia gravis.

13. Recent history of severe hepatic insufficiency, i.e., aspartate aminotransferase (AST)/alanine aminotransferase (ALT) above 3 times the upper limit of normal (ULN).

14. Recent history of severe renal insufficiency, i.e., serum creatinine value above 2.5 mg/dL.

15. History or presence of a severe infection, major surgery or trauma, severe metabolic, endocrine or electrolyte disturbances.

16. A major illness, requiring hospitalization during the 3 months before commencement of the screening period.

17. Inflammatory arthritis or other diseases known to cause intermittent or chronic pain. 18. Subjects who have had a recent history (less than 2 years before entering the study) of drug or alcohol abuse, or current positive urine drug screen. Alcohol abuse is defined as current consumption of more than three alcoholic beverages per day.

19. History of seizure disorder other than Infantile Febrile Seizures.

20. Disability claim for back pain, or pending legal issue regarding back pain.

21. Subjects who have received treatment with an investigational product/device within 30 days prior to study entry.

22. Subjects who have a history of allergic reaction to tolperisone, eperisone, or other skeletal muscle relaxants, lidocaine, acetaminophen or NSAIDs, or any components of these study medications.

23. Any other condition that, in the opinion of the Investigator, would adversely affect the subject’s ability to complete the study or its measures.

24. Subjects who are unwilling to stop taking moderate to potent inhibitors of cytochrome P450 (CYP) isozymes CYP2D6 and CYP2C19, which are likely to cause drug interactions with tolperisone HC1 (e.g., medications such as paroxetine and fluvoxamine).

25. Subjects who are a site staff member, relative, or friend of a site staff member or subjects in same household or who are related to each other.

26. Subjects with clinically significant cardiovascular disorders, such as ischemic heart disease, arrhythmias, poorly controlled hypertension, or history of acute myocardial infarction.

27. Subjects with QT interval greater than 480 milliseconds (msec) or greater than 450 msec if accompanied by a partial bundle branch block, or other clinically significant electrocardiogram (ECG) abnormaility at Screening in the judgement of the Investigator.

28. Subjects with diastolic blood pressure less than 50 mmHg or greater than 105 mmHg; sitting heart rate less than 50 beats per minute (bpm) or greater than 110 bpm (after approximately 3 minutes at rest); or heart rate by ECG less than 50 or greater than 110 bpm at Screening.

Restrictions [00159] Subjects were to abstain from using psychoactive prescription or non-prescription medications, psychoactive nutritional supplements or herbal preparations during their participation in the study.

[00160] Subjects were to abstain from using any medication or dietary supplement to promote sleep, including over the counter sleep medications, during their participation in the study.

[00161] Subject were to abstain from using antihistamine or any other drugs that can cause drowsiness, and will discuss any new prescription with the Investigator.

[00162] Subjects were to abstain from using moderate to potent inhibitors of CYP2D6 and CYP2C19, which are likely to cause drug interactions with tolperisone HC1 (e.g., medications such as paroxetine and fluvoxamine).

[00163] Other medications that the subject routinely takes are discussed and reviewed by the PI. All concomitant medication taken during the trial should be recorded with indication, daily dose, and start and stop dates of administration.

Study Design

[00164] The full schedule of procedures is provided in Table 8 below.

[00165] Subjects were screened for eligibility for participation in the study at the Screening/Baseline Visit 1 (Day 1) after reviewing and signing the informed consent form. Subjects meeting all inclusion/exclusion criteria are randomized into the study (Day 1) and begin dosing this same day. If needed, screening assessments were completed up to 3 days prior to Day 1 (first dose) as described below (Figure 3).

Interventions

[00166] The subjects are instructed to swallow the tablets whole, with approximately 4-6 ounces of water (with or without food).

• Subjects in Group A (n=80) are randomized to receive (1) 50 mg tolperisone tablet, TID for 14 days, for a total daily dose of 150 mg. • Subjects in Group B (n=80) are randomized to receive (1) 100 mg tolperisone tablet administered TID for 14 days, for a total daily dose of 300 mg.

• Subjects in Group C (n=80) are randomized to receive (1) 150 mg tolperisone tablet administered TID for 14 days, for a total daily dose of 450 mg.

• Subjects in Group D (n=80) are randomized to receive (1) 200 mg tolperisone tablet administered TID for 14 days, for a total daily dose of 600 mg.

• Subjects in Group E (n=80) are randomized to receive (1) placebo tablet administered TID for 14 days.

Randomization

[00167] Randomization will occur only after the subject is determined to be eligible for study participation based on the inclusion and exclusion criteria. Subjects are randomly assigned to one of the following five treatment groups in a 1 : 1 : 1 : 1 : 1 ratio: tolperisone 50 mg TID (150 mg/day), tolperisone 100 mg TID (300 mg/day), tolperisone 150 mg TID (450 mg/day), tolperisone 200 mg TID (600 mg/day), matching placebo TID. Prior to each eligible subject’s participation, the next unique, sequentially available randomization number is assigned to the subject using an interactive web response system.

Outcomes

Endpoints

[00168] Data for primary efficacy analysis is assessed during the clinic visits by the subject on the study-provisioned tablet provided to each site for use at baseline, and at Days 4 and 14. Additional efficacy endpoints and dosing are collected daily at specified times from the subjects via a smartphone/trial application for ePROs. At baseline, and at Days 4 and 14, efficacy endpoints are assessed during the clinic visit on the study-provisioned tablet provided to each site. See the Schedule of Procedures for all assessments to be conducted during the study. For the endpoints below, baseline is defined as the last assessment prior to the first dose of study drug.

Primary Efficacy Endpoint

[00169] Subject-rated pain “right now” due to acute back spasm using a Numerical Rating Scale (NRS; 0 10 scale, from no pain to worst possible pain) on Day 14. Secondary Efficacy Endpoints

• Subject-rated pain due to acute back spasm “right now” using NRS on Day 4.

• Subject-rated average pain due to acute back spasm over past 12 hours using NRS on Days 1 to 14, measured in morning and evening.

• Subject-rated average pain due to acute back spasm over past 1 hour using NRS on Days 1 to 14, measured in morning and evening.

• Subject-rated average pain at rest due to acute back spasm using NRS on Days 1 to 14, measured in evening.

• Subject-rated average pain on movement due to acute back spasm using NRS on Days 1 to 14, measured in evening.

• Subject rating of medication helpfulness (SRMH) using a scale of 1-5 on Days 4 and 14, where 1 = poor, 2 = fair, 3 = good, 4 = very good, and 5 = excellent.

• Time to relief of pain due to acute back spasm (days) from baseline using subject-rated NRS of pain over past 12 hours. The first NRS score of 2 or lower will be used to define relief.

• Clinician’s Global Impression of Severity (CGI-S) using 1-5 scale at baseline (Day 1), where 1 = no pain, 2 = mild pain, 3 = moderate pain, 4 = severe pain, and 5 = worst possible pain.

• Clinician’s Global Impression of Change (CGI-C) using a scale of 1-7 on Days 4 and 14, where 1 = very much worse, 2 = much worse, 3 = minimally worse, 4 = no change, 5 = minimally improved, 6 = much improved, and 7 = very much improved.

• Patient’s Global Impression of Severity (PGI-S) using a scale of 1-5 scale at baseline (Day 1), where 1 = no pain, 2 = mild pain, 3 = moderate pain, 4 = severe pain, and 5 = worst possible pain

• Patient’s Global Impression of Change (PGI-C) based on subject’s global assessment using a scale of 1-7 on Days 4 and 14, where 1 = very much worse, 2 = much worse, 3 = minimally worse, 4 = no change, 5 = minimally improved, 6 = much improved, and 7 = very much improved. • Fingers to floor distance (FFD) measured at Baseline (Day 1), Day 4, and Day 14. FFD is an index of mobility of the spinal cord measured as distance in cm when standing with the spinal cord flexed with complete extension of knee joint, on Days 4 and 14 compared to baseline (Day 1).

• Oswestry Pain and Disability (ODI) assessment at baseline (Day 1), Day 4, and Day 14.

The ODI questionnaire has 10 questions with one answer each for pain intensity, personal care, lifting, walking, sitting, standing, sleeping, sex life (if applicable), social life, and traveling. Scores were assigned for each section from 0 to 5 (5 being the worst case) and ODI scores were derived.

• Use of study-provided rescue medication (acetaminophen tablets [500 mg]) measured daily and assessed as number of rescue tablets administered by the subject and recorded via smartphone/use of trial application.

• Quality of sleep as rated by subjects daily from Day 1 to Day 14. The rating scale is 1-5, where 1 = not at all to 5 = slept all night. Assessments were collected via smartphone/use of trial application.

Secondary Safety Endpoints

• Adverse events (AEs) and serious adverse events (SAEs).

• Clinical evaluations including vital signs (blood pressure, heart rate, respiratory rate, body temperature), orthostatic effects on blood pressure, physical examinations, and 12 lead electrocardiogram (ECG).

• Laboratory tests including blood chemistry, hematology, and urinalysis.

• Visual Analogue Scale (VAS) for subject-reported sleepiness as measured in the clinic at Day 4 via tablet ePRO. Scale was from 0 to 10, where 0 = alert, wide awake to 10 = very sleepy, difficulty remaining awake.

[00170] Secondary Safety Analyses

[00171] Treatment-emergent and after-treatment AEs were to be summarized by treatment group.

The following summaries were to be presented: overall summary of TEAEs meeting various criteria,

TEAEs by MedDRA SOC and preferred term, TEAEs by severity grade, TEAEs by relationship to study drug, SAEs, TEAEs leading to study drug discontinuation, TEAEs by CYP4502D6 genotype, and after-treatment AEs. Separate data listings were to be provided for AEs, SAEs, AEs leading to discontinuation, interruption, or dose reduction of the study drug, and deaths. Treatment-emergent adverse events (TEAEs) were defined as AEs with onset on or after the first dose of study drug through 24 hours after the last dose of study drug or existing events that worsened during this period. Adverse events with onset greater than 24 hours (or > 1 day) after the date of the last dose of study drug through the date of the Follow-up Visit (Visit 4/Day 28) were considered after-treatment events.

Endpoint Assessment

Blood Collection for Tolperisone Plasma (PK) Concentrations (Optional)

[00172] In a subset of subjects (N=80) at select sites, blood samples for the determination of plasma tolperisone concentrations are drawn on Day 4 (Visit 2) after completion of all study assessments. The results from the analyses will be used for determination of population PK of tolperisone. Plasma samples are analyzed for tolperisone using a validated liquid chromatography with tandem mass spectrometric detection (LC/MS/MS) method (limit of quantification [LOQ]: 1 ng/mL).

Severity Assessment

[00173] All AEs were to be graded as mild, moderate, or severe according to the following definitions:

• Mild: Causing no limitation of usual activities; the subject may experience slight discomfort.

• Moderate: Causing some limitation of usual activities; the subject may experience annoying discomfort.

• Severe: Causing inability to carry out usual activities; the subject may experience intolerable discomfort or pain.

Causality Assessment

[00174] Investigators were required to assess the causal relationship (i.e., whether there was reasonable possibility that the study drug caused the event) using the following definitions: • Unrelated: another cause of the AE was more plausible; a temporal sequence could not be established with the onset of the AE and administration of the study agent; or a causal relationship was considered biologically implausible.

• Possibly Related: There is a clinically plausible time sequence between onset of the AE and administration of the study agent, but the AE could also be attributed to concurrent or underlying disease, or the use of other drugs or procedures. Possibly related was to be used when the study agent was one of several biologically plausible AE causes.

• Definitely Related: The AE was clearly related to use of the study agent.

Additional Results DNA Genotyping

[00175] Results are examined and summarized for CYP450 2D6 polymorphism, dose response, and AE profile.

Pharmacokinetic Analysis

[00176] Details of the PK and associated statistical analyses are included in a separate population PK Statistical Analysis Plan.

Biological Specimens

[00177] Whole blood samples and urine samples are collected as outlined in the Schedule of Procedures (Table 8) for clinical chemistry, hematology, urinalysis, and optional PK and DNA genotyping.

Table 8. Schedule of Procedures

EOT = End of Treatment; eCRF = electronic case report form; ePRO = electronic Patient Reported Outcomes; ET = Early Termination; FFD = Fingers to floor distance; NRS = Numeric Rating Scale; PK = pharmacokinetic. ^a Screening assessments may have been completed within 3 days prior to Day 1 (-3 to 0 days). If screening assessments were completed prior to Day 1, inclusion/exclusion criteria were to be re-reviewed for qualification of the subject’s enrollment into the study prior to dosing on Day 1. ^b Including sex, age, race, ethnicity, body weight (kg), height (cm), body mass index (BMI) (kg/m2), and smoking habits. ^c Physical and neurological examination were to be performed at Screening/Baseline (Day 1), on Day 4, and on Day 14. A physical examination was only to be performed on Day 28. A complete physical examination was to be performed at Screening/Baseline (Day 1). All other physical examinations may have been disease-specific and symptom directed. ^d Laboratory evaluations included hematology, serum chemistry, and urinalysis on Days 1 and 14. ^e DNA genotyping for CYP4502D6 polymorphism was to be collected at same time of other required blood draw on Day 1. ^f For the select group of sites and subjects who were to undergo PK assessments, blood samples were to be drawn on Day 4. ^g Dosing was to be 3 times per day, with a single tablet administered at each dose. Subjects were to be instructed to dose at 6-8 am, 12-2 pm, and 6-8 pm for 14 days and were to enter their dosing information in the eDiary on the subject’s smartphone/trial application.

¹¹ Subject rating of pain using Numerical Rating Scale (NRS, a scale of 0 to 10 where 0 = no pain, and 10 = worst possible pain) for the level of pain that the subject was feeling “right now” due to back spasm (primary efficacy endpoint) administered by study -provisioned tablet ePRO at baseline, and on Days 4 and 14 in the clinic.

¹ Subject rating of medication helpfulness (SRMH): a five point scale from 1 = poor to 5 = excellent, administered by study-provisioned tablet ePRO on Days 4 and 14 in the clinic, ^j Subject rating of pain using NRS due to back spasm, measured daily in the morning 8 to 10 am and in the evening between 8 to 10 pm from Days 1 through 14, for intensity of average pain due to spasm over last 12 hours, and subject rating of average pain over the past 1 hour, all on the subject’s smartphone/trial application. ^k Subject rating of average pain using NRS at rest and upon movement at the end of the day (between 8 to 10 pm) on Days 1 to 14 on the subject’s smartphone/trial application.

¹ Functionality assessments to be administered in the clinic on Days 1, 4 and 14. FFD is measured as distance in cm from the tips of the fingers to the floor when standing with the spinal cord flexed with complete extension of knee joint. This was not captured in an electronic device. Score was to be entered in the eCRF. ^m The Oswestry Disability Index (10 sections with one answer each for: pain intensity, personal care, lifting, walking, sitting, standing, sleeping, sex life [if applicable], social life, and traveling) was to be captured by study- provisioned tablet ePRO on Days 1, 4, and 14 in the clinic. ⁿ The use of study -provided rescue medication (acetaminophen 500 mg) taken to control their pain throughout the day was to be captured in the subject’s smartphone/trial application daily from Day 1 through 14, at the end of the day. Subjects were not to take rescue medications on clinic visits on Days 4 and 14.

⁰ The subject’s quality of sleep was to be captured on his or her smartphone/trial application starting at the Baseline Visit in clinic and on a daily basis at home/away from clinic between 8 to 10 am for Days 1 to 14. In response to the question of “how did you sleep last night”, subject responses were to be captured on a 5-point scale (from 1 = not at all to 5 = slept all night). ^p Vital signs included supine and standing blood pressure; sitting heart rate (after approximately 3 minutes at rest); respiratory rate; and body temperature on Days 1, 4, 14, and 28 (all visits). Weight and height were to be assessed at Visit 1 only.

Results

EFFICACY EVALUATION

[00178] Primary Endpoint Analysis - Patient Assessment of Pain “Right Now” at Day 14

[00179] In the primary analysis of the primary efficacy endpoint, the overall trend in NRS rating of pain “right now” across dose groups at Day 14 trended toward statistical significance (p = 0.0539). In the analysis of pairwise LSM estimates and LSMDs (Treatment - Placebo) for each tolperisone dose versus placebo, the observed values were -0.6 (p = 0.0240), -0.5 (p = 0.0506), -0.2 (p = 0.444), and -0.8 (p = 0.0040) for tolperisone 150 mg/day, 300 mg/day, 400 mg/day, and 600 mg/day, respectively. Three of the four doses were within range of expected results, with the greatest numerical difference and statistical significance noted between the tolperisone 600 mg/day and placebo.

SAFETY EVALUATION

[00180] Summary of Adverse Events

[00181] Eleven subjects (14.1%) in the placebo group experienced 13 TEAEs and 61 subjects (18.1%) in the total tolperisone group experienced 92 TEAEs.

[00182] All TEAEs in the placebo group and the maj ority of TEAEs in the total tolperisone group were mild or moderate.

[00183] Of the 19 subjects who were poor metabolizers of CYP450 2D6 (3 in the placebo group and 16 in the total tolperisone group), there were no subjects with TEAEs in the placebo group and only 2 subjects with TEAEs in the total tolperisone group (1 with headache in the 150 mg/day group and 1 with dizziness in the 300 mg/day group).

[00184] There were no apparent treatment- or dose-related trends or clinically meaningful findings with respect to changes in laboratory results, vital signs, ECGs, neurological examinations, or concomitant medication use. [00185] Treatment-emergent AEs by CYP4502D6 Genotype

[00186] Of the 19 subjects who were poor metabolizers of CYP450 2D6 (3 in the placebo group and 16 in the total tolperisone group), there were no subjects with TEAEs in the placebo group and only 2 subjects with TEAEs in the total tolperisone group. In the total tolperisone group, the incidences of TEAEs in poor metabolizers of CYP450 2D6 (12.5% [2/16]) and in all other subjects (11.0% [34/310]) were similar. Across tolperisone groups, the incidence of TEAEs in poor metabolizers of CYP450 2D6 was 25.0% (1/4), 20.0% (1/5), 0% (0/3), and 0% (0/4) in the 150 mg/day, 300 mg/day, 450 mg/day, and 600 mg/day groups, respectively.

[00187] These results in subjects determined to be poor metabolizers are surprising and unexpected because this population of patients (i.e., those with a particular CYP450 2D6 genotype) is expected to show higher levels of drug exposure, and therefore, more TEAEs. Past studies have shown that the CYP2D6 genotype (conferring ultra-fast, fast, intermediate and slow metabolizer phenotypes) was shown to influence tolperisone bioavailability. In one PK study, subjects who were classified as CYP2D6 intermediate metabolizers had approximately 50% higher exposure to tolperisone following oral dosing than fast metabolizers. Overall, the bioavailability increased with decreasing metabolic activity among the four genotypes. However, in the present Phase 2 evaluation of tolperisone, the higher levels of exposure expected in patients that are “poor metabolizers” was not accompanied by more TEAEs.

Table 13. Treatment-emergent Adverse Events Reported for at Least Two Subjects in the Total Tolperisone Group by CYP4502D6 Genotype, System Organ Class, and Preferred Term (Safety Population).

CONCLUSIONS

[00188] Treatment with tolperisone at daily doses of 150, 300, 450, and 600 mg taken orally for 14 days for relief of pain due to acute back muscle spasm was found to be efficacious at three of the four dose groups with the largest separation seen at the 600mg daily dose group versus placebo.

[00189] There were no deaths or SAEs during the study. The only TEAEs reported with an incidence of > 2% in the total tolperisone group were headache and diarrhea. The rates of somnolence and hypersensitivity were low (1.2%) in the total tolperisone group. Overall, there were no treatment- or dose-related trends noted for safety findings.

Claims

CLAIMS What is claimed is:

1. A method of treating muscle spasm associated with acute, painful musculoskeletal conditions in a patient in need thereof with tolperisone or a pharmaceutically acceptable salt thereof, the method comprising: orally administering to the patient at least a 5% decrease in an effective dosage amount of tolperisone or a pharmaceutically acceptable salt thereof when the patient is receiving a concomitant administration of a cytochrome P4502D6 (CYP2D6) inhibitor or a cytochrome P450 2C19 (CYP2C19) inhibitor, wherein the effective dosage amount is the dosage that would be recommended for a patient who is not concomitantly administered a CYP2D6 inhibitor or CYP2C19 inhibitor.

2. The method of claim 1, wherein there is an at least at a 20% decrease in an effective dosage amount of tolperisone or pharmaceutically acceptable salt thereof when the patient is receiving a concomitant administration of a CYP2D6 inhibitor or CYP2C19 inhibitor.

3. The method of claim 2, wherein the decrease in the effective dosage amount is a reduction of about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45% or about 45% to 50% of the tolperisone that would be recommended for a patient who is not concomitantly administered a CYP2D6 inhibitor or CYP2C19 inhibitor.

4. The method of any one of claims 1-3, wherein the dose of tolperisone or a pharmaceutically acceptable salt thereof without concomitant administration of the CYP2D6 inhibitor or the CYP2C19 inhibitor is from about 450 mg to 600 mg per day.

5. The method of any one of claims 1-4, wherein the effective dose of tolperisone or a pharmaceutically acceptable salt thereof administered to a patient receiving a concomitant administration of a cytochrome P4502D6 (CYP2D6) inhibitor or a cytochrome P4502C19 (CYP2C19) inhibitor is from about 150 mg to 400 mg per day.

6. The method any one of claims 1-5, wherein the patient is receiving a concomitant administration of a CYP2D6 inhibitor.

7. The method of claim 6, wherein the CYP2D6 inhibitor is selected from the group consisting of amiodarone, bupropion, chloroquine, cimetidine, cinacalcet, diphenhydramine, doxorubicin, fluoxetine, haloperidol, imatinib, metoclopramide, methadone, paroxetine, propafenone, propoxyphene, quinidine, ritonavir, terbinafme and thioridazine.

8. The method of claim 7, wherein the CYP2D6 inhibitor is paroxetine.

9. The method any one of claims 1-5, wherein the patient is receiving a concomitant administration of a CYP2C19 inhibitor.

10. The method of claim 9, wherein the CYP2C19 inhibitor is selected from the group consisting of chloramphenicol, cimetidine, clopidogrel, delavirdine, efavirenz, esomeprazole, felbamate, fluconazole, fluoxetine, fluvoxamine, isoniazid, moclobemide, modafmil, omeprazole, oxcarbazepine, ticlopidine, and voriconazole.

11. The method of claim 10, wherein the CYP2C19 inhibitor is fluvoxamine.

12 A method of safely administering tolperisone or a pharmaceutically acceptable salt thereof for the treatment of muscle spasm associated with acute, painful musculoskeletal conditions in a patient who is being administered tolperisone, the method comprising: determining if the patient has taken or will take, a concomitant dose of a CYP2D6) inhibitor or a cytochrome P4502C19 (CYP2C19 inhibitor and orally administering to the patient an at least a 5% decrease in an effective dosage amount of tolperisone or a pharmaceutically acceptable salt thereof when the patient is receiving a concomitant administration of a CYP2D6 inhibitor or a CYP2C19 inhibitor, wherein the effective dosage amount is the dosage that would be recommended for a patient who is not concomitantly administered a CYP2D6 inhibitor or CYP2C19 inhibitor.

13. The method of claim 12, wherein the decrease in the effective dosage amount is a reduction of at least 20 of the tolperisone that would be recommended for a patient who is not concomitantly administered a CYP2D6 inhibitor or CYP2C19 inhibitor.

14. The method of claim 12, wherein the CYP2D6 inhibitor or a CYP2C19 inhibitor is administered within two weeks of administration of tolperisone or a pharmaceutically acceptable salt thereof.

15. The method of claim 12, wherein the CYP2D6 inhibitor or a CYP2C19 inhibitor is administered within three days of administration of tolperisone or a pharmaceutically acceptable salt thereof.

16. The method of claim 12, further comprising administering a dose of about 300 mg per day of tolperisone or a pharmaceutically acceptable salt thereof when the patient is receiving a concomitant administration of a CYP2D6 inhibitor or a CYP2C19 inhibitor.

17. The method of claim 16, further comprising administering about 100 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d. when the patient is receiving a concomitant administration of a CYP2D6 inhibitor or a CYP2C19 inhibitor

18. A method for treating a patient with muscle spasm associated with acute, painful musculoskeletal conditions, the method comprising: administering a therapeutically effective amount of a composition comprising a daily dose of about 450 mg to 600 mg tolperisone or a pharmaceutically acceptable salt thereof; determining if the patient is being administered a CYP2D6 inhibitor or a CYP2C19 inhibitor; warning of a potential drug/drug interaction due to the combination of the CYP2D6 inhibitor or a CYP2C19 inhibitor and tolperisone; and recommending reducing the dose of tolperisone by at least about 5%.

19. The method of claim 18, wherein the CYP2D6 inhibitor or a CYP2C19 inhibitor is administered within two weeks of administration of tolperisone or a pharmaceutically acceptable salt thereof.

20. The method of claim 18, wherein the CYP2D6 inhibitor or a CYP2C19 inhibitor is administered within three days of administration of tolperisone or a pharmaceutically acceptable salt thereof.

21. The method of any of claims 1-20, wherein the tolperisone comprises tolperisone hydrochloride.

22. The method of any of claims 1-20, wherein the tolperisone is provided in a composition comprising tolperisone hydrochloride, citric acid anhydrous, lactose anhydrous, stearic acid, starch pregelatinized, crospovidone, polyethylene glycol 6000, hypromellose, lactose monohydrate, titanium dioxide, and macrogol PEG.

23. A method of safely administering tolperisone or a pharmaceutically acceptable salt thereof for the treatment of muscle spasm associated with acute, painful musculoskeletal conditions in a patient in need thereof, the method comprising: determining whether the patient is a cytochrome P4502D6 (CYP2D6) poor metabolizer by determining if the patient has a CYP2D6 poor metabolizer genotype; if the patient has a CYP2D6 poor metabolizer genotype, then orally administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof that is the same daily dose as a patient who does not have a CYP2D6 poor metabolizer genotype.

24. The method of claim 23, wherein the administered daily dose of tolperisone or a pharmaceutically acceptable salt thereof is from about 450 mg to 600 mg per day.

25. The method of any one of claims 23-24, wherein the administration to the patient having a CYP2D6 poor metabolizer genotype provides about the same incidence of adverse events related to treatment with tolperisone as observed in patients not having a CYP2D6 poor metabolizer genotype who are administered the same tolperisone dose.

26. The method of any one of claims 23-25, wherein the administration to the patient having a CYP2D6 poor metabolizer genotype does not increase the incidence of somnolence compared to the incidence of somnolence patients not having a CYP2D6 poor metabolizer genotype who are administered the same tolperisone dose.

27. The method of any one of claims 23-26, wherein the CYP2D6 poor metabolizer genotype is selected from the group consisting of CYP2D6*4, *9, *10, *17, *29 and *41.

28. The method of claim 27, wherein the CYP2D6 poor metabolizer genotype is CYP2D6*4.

29. The method of claim 27, wherein the CYP2D6 poor metabolizer genotype is CYP2D6*10.

30. The method of claim 24, wherein the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day comprises administering about 600 mg of tolperisone or a pharmaceutically acceptable salt thereof.

31. The method of claim 24, wherein the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day comprises administering about 450 mg of tolperisone or a pharmaceutically acceptable salt thereof.

32. The method of claim 24, wherein the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day comprises administering about 200 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d.

33. The method of claim 24, wherein the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day comprises administering about 150 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d.

34. A method of treating muscle spasm associated with acute, painful musculoskeletal conditions in a patient in need thereof with tolperisone or a pharmaceutically acceptable salt thereof, the method comprising: orally administering to a patient receiving concomitant administration of a cytochrome P4502D6 (CYP2D6) inhibitor or a cytochrome P4502C19 (CYP2C19) inhibitor the same effective dosage amount of tolperisone or a pharmaceutically acceptable salt thereof received by a patient not receiving concomitant administration of a cytochrome P4502D6 (CYP2D6) inhibitor or a cytochrome P4502C19 (CYP2C19) inhibitor.

35. The method of claim 34, wherein the effective dose of tolperisone or a pharmaceutically acceptable salt thereof is from about 450 mg to 600 mg per day.

36. The method of claim 35, wherein the step of administering an effective dose of tolperisone or a pharmaceutically acceptable salt thereof comprises administering about 200 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d.

37. The method of claim 35, wherein the step of administering an effective dose of tolperisone or a pharmaceutically acceptable salt thereof comprises administering about 150 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d.

38. The method of any one of claims 34-37, wherein the patient is receiving a concomitant administration of a CYP2D6 inhibitor.

39. The method of claim 38, wherein the CYP2D6 inhibitor is selected from the group consisting of amiodarone, bupropion, chloroquine, cimetidine, cinacalcet, diphenhydramine, doxorubicin, fluoxetine, haloperidol, imatinib, metoclopramide, methadone, paroxetine, propafenone, propoxyphene, quinidine, ritonavir, terbinafme and thioridazine.

40. The method of claim 39, wherein the CYP2D6 inhibitor is paroxetine.

41. The method of any one of claims 34-37, wherein the patient is receiving a concomitant administration of a CYP2C19 inhibitor.

42. The method of claim 41, wherein the CYP2C19 inhibitor is selected from the group consisting of chloramphenicol, cimetidine, clopidogrel, delavirdine, efavirenz, esomeprazole, felbamate, fluconazole, fluoxetine, fluvoxamine, isoniazid, moclobemide, modafmil, omeprazole, oxcarbazepine, ticlopidine, and voriconazole.

43. The method of claim 42, wherein the CYP2C19inhibitor is fluvoxamine.

44. The method of any one of claims 34-43, wherein orally administering to a patient receiving concomitant administration of an effective dosage amount of tolperisone or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor or a CYP2C19 inhibitor provides about the same incidence of adverse events related to treatment observed as a patient receiving the same effective dose of tolperisone or a pharmaceutically acceptable salt thereof not receiving concomitant administration of a CYP2D6 inhibitor or a CYP2C19 inhibitor.

45. A method of safely administering tolperisone or a pharmaceutically acceptable salt thereof for the treatment of muscle spasm associated with acute, painful musculoskeletal conditions in a patient in need thereof, the method comprising: determining whether the patient is a CYP2D6 poor metabolizer by determining if the patient has a CYP2D6 poor metabolizer genotype; if the patient has CYP2D6 poor metabolizer genotype, then orally administer a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 150 mg to 400 mg per day; and if the patient does not have a CYP2D6 poor metabolizer genotype, then orally administer a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 450 mg to 600 mg per day.

46. The method of claim 45, wherein the CYP2D6 poor metabolizer genotype is selected from the group consisting of CYP2D6*4, *9, *10, *17, *29 and *41.

47. The method of claim 46, wherein the CYP2D6 poor metabolizer genotype is CYP2D6*4.

48. The method of claim 46, wherein the CYP2D6 poor metabolizer genotype is CYP2D6*10.

49. The method of claim 45, wherein the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 150 mg to 400 mg per day comprises administering about 400 mg of tolperisone or a pharmaceutically acceptable salt thereof.

50. The method of claim 45, wherein the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 150 mg to 400 mg per day comprises administering about 300 mg of tolperisone or a pharmaceutically acceptable salt thereof.

51. The method of claim 45, wherein the step of administering a daily dose of tolperisone or a pharmaceutically acceptable salt thereof from about 150 mg to 400 mg per day comprises administering about 100 mg of tolperisone or a pharmaceutically acceptable salt thereof t.i.d.