TW201320994A - Dosage regimen - Google Patents

Abstract

S1P receptor modulators or agonists are administered following a dosage regimen whereby during the initial days of treatment the daily dosage is lower than the standard daily dosage.

Description

Medication treatment

The present invention relates to a SIP receptor modulator or agonist (such as fingolimod (FTY720)), for example, for treating an autoimmune disease or condition (such as multiple sclerosis (MS)) The patient.

Fingolimod ^{(FTY720; Gilenya TM; Novartis Pharma} AG, Basel, Switzerland) based sphingosine-1 -phosphate receptor modulators. Fingolimod 0.5 mg once daily is the first oral therapy approved in many countries for the relief of multiple sclerosis and for high activity relapsing-remitting MS (RRMS) in the European Union.

Multiple sclerosis is the main cause of neurological diseases in young people and the most common central nervous system myelin loss. Existing therapies, such as interferon-[beta] and glatiramer acetate, have only moderate efficacy and thus show only minor effects on disease progression. In addition, such biological agents are administered parenterally and are associated with certain adverse effects such as, for example, local reactions at the site of injection and fever symptoms. Therefore, medically urgently requires effective oral treatment for multiple sclerosis.

When first administered, fingolimod can produce a negative chronotropic effect, ie, reduce the heart rhythm, such as, for example, "FTY720: Placebo-Controlled Study of the Effect on Cardiac Rate and Rhythm in Healthy Subjects", Robert Schmouder, Denise Serra, Yibin Wang, John M. Kovarik, John DiMarco, Thomas L. Hunt and Marie-Claude Bastien. J. Clin. Pharmacol. 2006; 46; 895. For example, administration of 1.25 mg FTY720 can cause a heart rate drop of about 8 hops per minute (BPM). This effect can be at the beginning Occurs in the case of a second dose of fingolimod, and when the drug treatment is started again after a few days or more.

Therefore, fingolimod therapy is preferably followed by close medical supervision for several hours to verify that the heart rhythm of patients who have received fingolimod is maintained at an acceptable level. This may require the patient to be hospitalized, which in turn makes the treatment more expensive and complicated. There is a need to reduce the time required for medical supervision after the first dose of fingolimod, and even better to exclude supervision or limit it to the type of patient.

Titration treatments which alleviate this effect have been described, in particular, in WO 2010/075239, the contents of which are incorporated herein by reference. Although this treatment allows for a reduction in the time-dependent effects associated with the first administration of fingolimod, an improved titration regime still needs to be developed.

It has now surprisingly been found that when the S1P receptor modulators or agonists of the invention are used to treat a patient suffering from an autoimmune disease or condition (eg, multiple sclerosis), the prescribed dosing regimen will provide additional Unexpected benefits. In particular, the dosing regimen of the present invention allows for a significant reduction or even complete elimination of the negative chronotropic effects associated with the first administration of fingolimod, for example, reducing or eliminating after a first administration or a few days or more of interruption The need to monitor for hours after restarting medical treatment.

Administration of fingolimod to a given dosing regimen in accordance with the present invention may also significantly reduce or even completely eliminate the risk of room-room (AV) blockage or cardiac arrest in patients receiving this compound.

In addition, the prescribed dosing regimen of the present invention allows for the administration of fingolimod to a patient type that may be less suitable in other circumstances. In the invention In a specific embodiment, the titration treatment is administered to a patient who is susceptible to or suffering from heart failure or arrhythmia, a patient with a high grade of atrioventricular occlusion or diseased sinus syndrome, a patient with a history of syncope episodes, or is receiving A beta blocker or a patient treated with antiarrhythmia, such as a patient receiving an antiarrhythmic drug. The titration treatment of the present invention can also maintain a patient with a discontinuation treatment or a treatment leave, for example, a vacation of more than 4 days, more than 6, 7, 8, 10, 12 or 14 days, for example, an interruption time of at least 4 days, for example, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 10 days, at least 12 days or at least 14 days.

The administration regimen of the present invention is used in the course of the start of fingolimod therapy, which achieves a standard fingolimod treatment dose range and has as little negative as possible associated with fingolimod therapy. Time-varying effect and / or AV blocking effect.

S1P receptor modulator or agonist

Preferably, the S1P receptor agonist or modulator is fingolimod (FTY720), ie 2-amino-2-[2-(4) in free form or in the form of its pharmaceutically acceptable salt or phosphate derivative. -octylphenyl)ethyl]propane-1,3-diol.

In one embodiment of the invention, the S1P receptor modulator is FTY720 hydrochloride as follows:

In another embodiment of the invention, the S1P receptor modulator is a phosphate derivative of fingolimod, such as FTY720-phosphate, as follows:

Medication treatment

As described above, the present invention provides a novel administration regimen suitable for minimizing negative chronotropic effects and/or AV occlusion effects that may be associated with S1P receptor modulator or agonist therapy.

Cardiac effects include AV blockage, which includes first degree AV blockage (eg, PR interval greater than 0.2 seconds) and second degree AV blockage, such as first degree AV blockage. Cardiac effects include a heartbeat pause, for example, a heartbeat pause of more than 2 seconds.

According to the present invention, there is provided a use of an S1P receptor modulator or agonist for the manufacture of a medicament whereby the medicament is administered in a manner that the dose during the start of treatment is lower than the therapeutic daily dose and is gradually or only increased once as needed Large doses up to the standard daily dose, wherein the treatment initiation period is at least 2 weeks, for example, at least 4 weeks, such as 4 weeks. The treatment then preferably continues to use a standard daily dose of the S1P receptor modulator or agonist.

Preferably, at the beginning of the treatment, the agent is administered according to a course of administration to reduce the heart rate (e.g., mean or minimum hedonic rate) daily or to be clinically insignificant, or to make the sinus rhythm of the patient normal. For example, the daily rate of heart rate (eg, average or minimum hedonic rate) may be less than about 6 to 7 bpm, for example, less than about 6, for example, 6 bpm, for example, less than about 5 bpm, for example, less than about 4 bpm, for example, less than about 3 bpm. Or less than about 2 bpm. For example, the titration therapy of the present invention is administered in a manner such that the heart rate can be reduced by 2 to 7 bpm, for example 2 to 6 bpm, for example 3 to 5 bpm.

The term "normal sinus rhythm" refers to the sinus rhythm of a patient when not receiving treatment. Assessment of normal sinus rhythm is within the physician's ability. Normal sinus rhythm typically produces a heart rate in the range of 60 to 100 bpm.

According to the present invention, "the beginning of treatment" means the period during which the S1P receptor modulator or agonist is administered at a dose lower than the therapeutic daily dose. Preferably, the "start of treatment" begins with the first administration of an S1P receptor modulator or agonist.

The duration of the start of treatment is at least 2 weeks, such as at least 4 weeks. For example, the treatment initiation period is up to 30 days, such as 28 days, such as 29 days. The duration of the start of treatment may also be about four weeks, for example, about one month, such as five weeks, such as more than one month, such as two months. In another embodiment, the treatment initiation period is from 7 to 30 days, such as from 7 to 28 days, such as from 1 to 2 weeks or from 7 to 14 days. The start of treatment can also be 2 to 3 weeks, or 3 to 4 weeks. It can also be 1 to 4 weeks or 2 to 4 weeks.

As defined herein, a therapeutic daily dose (also referred to as a standard daily dose) refers to a daily maintenance dose of the drug required to administer or treat a disease to be treated or prevented. Suitably, the therapeutic daily dose corresponds to a therapeutically effective dose.

A therapeutically effective dose means an S1P receptor modulator required to effectively treat a disease or condition of interest (i.e., exhibiting a rebound or symptom of a disease that is to be treated or prevented in an individual, and preferably exhibiting no signs or symptoms at all). Or agonist dose.

The S1 P receptor modulator or agonist of the present invention may be up to 10 times lower than the standard therapeutic dose during the initial period of treatment, for example up to 9 times lower than the therapeutic dose, for example up to 9 times lower, for example up to 8 times lower, for example 8 lower Between 9 times, for example up to 4 times as low, for example 4 times lower, for example a dose lower than 2 times.

Preferably, the dosage of the S1 P receptor modulator or agonist of the invention during the initial period of treatment is determined to increase incrementally up to the standard daily dose of the S1P receptor modulator or agonist. Preferably, the dose of the S1 P receptor modulator or agonist is increased at least once during the start of treatment as defined above, for example during the first 2 weeks or 4 weeks or longer. In one embodiment, the same dose is administered during the first week or the first 2 weeks of treatment, and then the increased dose is administered over the next few weeks, for example, the next 2 weeks. For example, a first dose that is at least 4 times lower than the therapeutic dose is administered within 2 weeks and a second dose that is at least 2 times lower than the therapeutic dose is administered over the next two weeks.

During the beginning of the treatment period, about 1.5 or more times, for example 2 or more times, for example 2 times the dose, of each previous dose may be used. For example, the first administered dose can be four times lower than the therapeutic dose, and the subsequent administered dose can be two times lower than the therapeutic dose, and the therapeutic dose is subsequently administered.

The same dose can be administered for a period of, for example, one week, such as at least one week, such as two weeks, such as at least two weeks, and then the dosage is further increased.

For example, during the initial period, the dosage may be between about 10 times, about 9 times or less about 9 to 8 times lower than the standard daily dose, for example, a therapeutic dose, for example, for a week or two. Subsequently, the dose can be increased to a certain daily dose, which is about 4 times lower than the standard daily dose, for example for a week or two. The subsequent dose can be further increased to a certain daily dose which is about 2 times lower than the standard daily dose, for example for a week or two. The treatment can then be continued at a standard daily dose. If desired, the daily dose can be further increased to a certain daily dose prior to administration of the standard daily dose, which is about 1.5 times lower than the standard daily dose, for example, for one week or two weeks.

In another embodiment of the invention, a more standard daily dose is administered, such as The therapeutic dose is about 4 times lower, for example for one, two or four weeks, and then administered an increased dose that is about 2 times lower than the standard daily dose, for example for a week or 2 or 4 weeks. The treatment is then carried out at a standard daily dose.

The same dose can be administered within 1, 2, 3 or 4 weeks of treatment, and then the dose is increased, preferably within 2 to 4 weeks of treatment. Suitably, each subsequent incremental dose is administered for 1, 2, 3 or 4 weeks, preferably for 2 or 4 weeks. In a particular embodiment, each subsequent incremental dose is administered after one week.

One or more dose increases can be made, such as up to 10 dose increases, such as up to 8 dose increases, such as up to 6 dose increases, such as up to 5 dose increases, up to 4 times The dose is increased and up to 3 doses are increased until the standard daily dose is reached. For example, it may be provided 1 to 4 times, for example 2 to 4 times, for example, one, two, three or four dose increases.

In a particular embodiment, the S1P receptor agonist is fingolimod (FTY720); a pharmaceutically acceptable salt thereof, such as the hydrochloride salt thereof; or a phosphate derivative thereof, for example, FTY720-phosphate.

For fingolimod, for example, in the case of its hydrochloride, an example of a standard daily dose may be a daily dose of up to 0.5 mg, for example, the dose may be 0.5 mg, such as 0.25 mg.

According to a preferred embodiment of the invention, the highest dose of the S1 P receptor modulator or agonist of the invention provided during the period prior to administration of the therapeutic dose may be up to 0.4 mg, for example up to 0.35 mg or up to 0.25 mg, For example, about 0.310 mg, such as about 0.325 mg, such as about 0.355 mg, such as about 0.375 mg.

According to the invention, the highest first dose can be between 0.01 mg and 0.30 mg Between, for example, between 0.01 mg and 0.15 mg, for example between 0.050 mg and 0.125 mg, for example between 0.050 mg and 0.125 mg. The highest first dose can be about 0.1 mg, such as about 0.125 mg, such as about 0.06 mg.

A particularly preferred dosage range for an S1 P receptor modulator or agonist of the invention, as defined above, is, for example, 0.1 to 0.5 mg, or 0.125 to 0.250 mg, or 0.125 to 0.375 mg, or 0.125 to 0.500 mg. , or 0.25 to 0.50 mg, or 0.06 to 0.50 mg, or 0.125 to 0.250 mg, or 0.060 to 0.125 mg, or 0.060 to 0.250 mg or 0.060 to 0.375 mg.

For example, the course of treatment is 0.125 mg/0.25 mg each, and the same dose is given for one week during the beginning of 2 weeks, or the same dose is given for 2 weeks during the beginning of one month. The treatment is then continued at a standard daily dose, such as a dose of 0.5 mg.

Alternatively, the course of treatment may each be 0.125 mg / 0.25 mg / 0.375 mg, for example, within the beginning of 3 weeks or longer, for example, administration of the same dose for one or two weeks. The treatment is then continued at a standard daily dose, such as a 0.5 mg dose.

In another embodiment, the course of treatment may each be 0.06 mg / 0.125 mg / 0.25 mg / 0.375 mg, for example, within the beginning of 4 weeks or longer, for example, administration of the same dose for one or two weeks. The treatment is then continued at a standard daily dose, such as 0.5 mg.

These treatments are especially suitable for FTY720 or FTY720 hydrochloride.

Preferred agents include agents for patients suffering from chronic chronic diseases such as autoimmune diseases such as multiple sclerosis, polymyositis, lupus nephritis, rheumatoid arthritis, inflammatory bowel disease or psoriasis. In one embodiment of the invention, the medicament is for a patient suffering from multiple sclerosis, For example, relapsing-remitting multiple sclerosis (RRMS) or primary progressive multiple sclerosis (PPMS), for example, for patients suffering from RRMS.

The administration procedure of the present invention is particularly useful for treating patients at risk of cardiac side effects, for example, patients with heart failure, risk of arrhythmia, patients with high grade atrioventricular blockage or sick sinus syndrome, and history of syncope episodes Patients who are in need or who are receiving beta blockers or who are in need or are receiving antiarrhythmic therapy, such as quinidine, procainamide (eg, quinidine, procainamide) Procainamide)) or a class III antiarrhythmic drug (eg, amiodarone, sotalol).

In a series of more specific or alternative embodiments, the invention also provides:

1.1 The S1P receptor modulator or agonist of the invention, preferably in free form or in the form of a pharmaceutically acceptable salt, of the use of fingolimod, such as the hydrochloride thereof, in the manufacture of a medicament, whereby the medicament is as above As agreed in the text.

1.2 The S1P receptor modulator or agonist of the invention, preferably in free form or in the form of a pharmaceutically acceptable salt, of the use of fingolimod, such as the hydrochloride thereof, in the manufacture of a medicament whereby the agent is In the beginning of at least 2 weeks, for example, within 4 weeks, the daily dose is administered below the therapeutic daily dose, and then the therapeutic daily dose is administered.

1.3 The S1P receptor modulator or agonist of the invention, preferably in free form or in the form of a pharmaceutically acceptable salt, fingolimod, or a phosphate derivative thereof, such as the hydrochloride thereof, for use in the manufacture of a medicament Thereby, the medicament is first administered in a certain manner, and then administered to the therapeutic daily dose, the administration agent The amount is gradually increased with at least one dose increment, and the same dose is administered for at least one week, for example for two weeks, and then increased.

1.4 The S1P receptor modulator or agonist of the invention, preferably in free form or in the form of a pharmaceutically acceptable salt, fingolimod, or a phosphate derivative thereof, such as the hydrochloride thereof, for use in the manufacture of a medicament Thereby, the agent is administered in such a way that the first administration dose is at least 4 times lower than the therapeutic dose, for example at least 9 times lower, for example between 9 and 8 times lower and the administration lasts for at least one week.

1.5 The S1P receptor modulator or agonist of the invention, preferably in free form or in the form of a pharmaceutically acceptable salt, fingolimod, or a phosphate derivative thereof, such as the hydrochloride thereof, for use in the manufacture of a medicament Thereby, the medicament is administered in a certain manner and then administered to the therapeutic dose, and the first dose is administered at least 4 times lower than the therapeutic dose for 2 weeks, and the administration dose is lower than the therapeutic dose in the next 2 weeks. At least 2 times the second dose.

1.6 The use of a SIP receptor modulator or agonist of the invention, preferably in free form or in the form of a pharmaceutically acceptable salt, of fingolimod, or a phosphate derivative thereof, for example a hydrochloride thereof, in the manufacture of a medicament Thereby, the medicament is administered in a manner such that the dose of the SIP receptor modulator or agonist does not exceed the standard daily dose of the S1P receptor modulator or agonist within 2 to 4 weeks from the start of treatment 10% or no more than 25%.

1.7 The use of an S1P receptor modulator or agonist as defined in 1.1 to 1.6 for the manufacture of a medicament whereby the medicament is administered to the patient in a manner to limit the possible risk of AV obstruction or Reduced to a clinically insignificant level.

1.8 The use of an S1P receptor modulator or agonist as defined in 1.1 to 1.6 for the manufacture of a medicament whereby the medicament is administered to the patient in a manner such that the sinus rhythm of the patient is normal .

1.9 For purposes as defined in 1.1 to 1.8, where the treatment begins for up to 2 weeks and is as long as one month or longer.

1.10 Use as defined in 1.1 to 1.9, where the agent is administered to a patient at risk of heart failure or AV blockage.

1.11 A use as defined in 1.1 to 1.9, wherein the agent is administered to a patient suffering from symptoms including dizziness, fatigue, and palpitations.

1.12 Use as defined in 1.1 to 1.9, wherein the agent is administered to a patient with a high grade of atrioventricular occlusion or diseased sinus syndrome.

1.13 The use as defined in 1.1 to 1.9, wherein the agent is given arrhythmia, such as the need for or receiving type Ia (eg, quinidine, procainamide) or a class III antiarrhythmic drug (eg Patients treated with amiodarone, sotalol or patients who require or are receiving beta-blocker therapy.

1.14 The use as defined in 1.1 to 1.9, wherein the agent is administered to a patient, for example, a patient suffering from multiple sclerosis, wherein fingolimod or its hydrochloride is in free form or in the form of a pharmaceutically acceptable salt The administration has been stopped for more than 10 days, for example more than 12 days, for example more than 14 days.

1.15 The use of fingolimod or a hydrochloride thereof in a free form or in a pharmaceutically acceptable form for the manufacture of a medicament, whereby the medicament is about 0.5 mg as defined above after the start of treatment as defined above or Smaller daily doses are administered.

1.16 for use as defined in 1.1 to 1.15 for the treatment of chronic chronic diseases A disease, such as an autoimmune disease, such as multiple sclerosis, such as RRMS.

2.1 A method of treating a chronic long-term disease (eg, an autoimmune disease, such as multiple sclerosis, eg, RRMS) as defined above, comprising administering to the individual a dose of up to 10 times less than a standard daily dose. Starting the treatment for at least 2 weeks, such as one month or longer, and then the S1P receptor modulator or agonist of the invention, for example, fingolimod, in free form or in a pharmaceutically acceptable form, such as its hydrochloride Daily dose.

2.2 A method of ameliorating or preventing negative side effects associated with the use of fingolimod for the treatment of an individual suffering from an autoimmune disease, comprising fingolimo in a free form or in a pharmaceutically acceptable form during the initial period of treatment De, for example, its hydrochloride, is administered to a needy individual at a lower daily dose than the standard daily dose and gradually increases the daily dose to a standard daily dose, wherein the initial period is at least 2 weeks, such as one month or longer .

2.3 A method as defined in 2.1 or 2.2 for the treatment of multiple sclerosis.

2.4 The method as defined in 2.1 to 2.3, wherein the S1P receptor modulator or agonist is in a free form of fingolimod or a pharmaceutically acceptable salt thereof, such as a hydrochloride salt, or a FTY720 phosphate, and is at the beginning After the course of treatment, it is administered at a dose of about 0.5 mg or less as defined above.

2.5 A method for ameliorating or preventing negative side effects associated with the use of fingolimod for the treatment of autoimmune diseases, the method comprising a period of less than a standard daily dose during a treatment initiation period of at least 2 weeks or a month Dosing is administered in a free form of fingolimod or a pharmaceutically acceptable salt thereof, such as a hydrochloride salt, or a FTY720 phosphate, and such daily dose is optionally taken Gradually increase to the standard daily dose.

2.6 A method of treating a chronic long-term disease as defined above, for example, an autoimmune disease, such as multiple sclerosis, such as RRMS, in a patient having a risk of heart failure, the method comprising administering a medication regimen as defined herein And an S1P receptor modulator or agonist of the invention.

3.0 A pharmaceutical composition comprising fingolimod or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, in a free form, or a FTY720 phosphate, for use in treating a chronic disease in a patient whereby the composition comprises a ratio The standard daily therapeutic dose is up to 10 times the daily dose, and whereby the composition is administered within about one month, such as 28 days, and then fingolimod is administered at a standard daily therapeutic dose.

In another embodiment of the present invention, provided

4.0 A kit comprising a daily pharmaceutical unit comprising different daily doses of an S1 P receptor modulator or agonist of the invention, for example, fingolimod or a pharmaceutically acceptable salt thereof, such as a salt, in free form The acid salt, or FTY720 phosphate, whereby the dose is below the standard daily dose, and each of the doses is administered for one week or for two weeks. For example, the kit comprises a unit dose of 0.125 mg fingolimod and a unit dose of 0.25 mg fingolimod. The kit may further comprise a unit dose of 0.375 mg fingolimod. The kit contains a unit dose of 0.5 mg fingolimod as needed.

4.1 A kit comprising a pharmaceutical unit comprising an S1P receptor modulator or agonist as defined herein for administration in accordance with a dosing regimen as defined herein, whereby as defined above rule One or more low dose units of a standard daily dose lower than the S1P receptor agonist of the present invention are provided during the first period of treatment, such as during the first month of treatment.

4.2 A kit comprising a unit of medicament comprising an S1P receptor modulator or agonist as defined herein, having a different daily dose, whereby the kit comprises a) at least one of: a standard day of about 1/8, about 1/4, about 1/2, about 1/1.5 of the S1P receptor modulator or agonist, and b) an optional S1P receptor modulator or agonist Dosage unit. Each dose can be administered for at least one week, for example two weeks.

4.3 A kit comprising a unit of medicament comprising a different amount of a S1P receptor modulator or agonist as defined herein, whereby the kit comprises a) about 1/ of a standard dose, respectively. 4 and about 1/2 of the S1P receptor modulator or agonist, and b) a standard daily dosage unit of an S1P receptor modulator or agonist as desired, and each of which may be administered for at least one week, for example two weeks.

4.4 a kit as defined in the above 4.0 to 4.3, which comprises fingolimod in free form or in the form of a pharmaceutically acceptable salt, for example a hydrochloride thereof, wherein the kit comprises at least one of 0.4 mg, 0.35 mg or A unit dose of 0.25 mg fingolimod, for example, contains 7 to 14 unit doses containing 0.4 mg, 0.35 mg, or 0.25 mg fingolimod.

4.5 A kit as defined in the above 4.0 to 4.3, which comprises fingolimod in free form or in the form of a pharmaceutically acceptable salt, for example a hydrochloride thereof, wherein the kit contains at least one of about 0.310 mg, 0.325 mg a unit dose of 0.355 mg or 0.375 mg of fingolimod, for example containing 7 to 14 A unit dose containing 0.310 mg, 0.325 mg, 0.355 mg, or 0.375 mg of fingolimod.

4.6 A kit as defined in the above 4.0 to 4.3, which comprises fingolimod in free form or in the form of a pharmaceutically acceptable salt, for example a hydrochloride thereof, wherein the kit contains at least one fingolimod containing 0.06 mg A unit dose, for example, the kit contains 7 to 14 unit doses containing 0.06 mg fingolimod.

4.7 A kit comprising a dosage unit of fingolimod, such as a hydrochloride salt, in free form or in the form of a pharmaceutically acceptable salt, wherein the kit comprises a) 7 to 14 ffolimods containing 0.125 mg Dosage unit, and b) 7 to 14 dosage units containing 0.25 mg fingolimod and, if desired, a dosage unit containing 0.5 mg fingolimod. For example, the kit comprises 14 dosage units containing 0.125 mg fingolimod, and 14 dosage units containing 0.25 mg fingolimod; or 7 dosage units having intensity of each dose.

4.8 A kit comprising a dosage unit of fingolimod, such as a hydrochloride salt, in free form or in the form of a pharmaceutically acceptable salt, wherein the kit comprises a) 7 to 14 ffolimods containing 0.125 mg Dosage unit; b) 7 to 14 dosage units containing 0.25 mg fingolimod, c) 7 to 14 dosage units containing 0.375 mg fingolimod, and optionally 0.5 mg fingolimod dose unit. For example, the kit contains seven dosage units containing 0.125 mg fingolimod, seven dosage units containing 0.25 mg fingolimod and seven dosage units containing 0.325 mg fingolimod; or 14 each Dosage unit for dose strength.

4.9 a fingomo containing in free form or in the form of a pharmaceutically acceptable salt In the case of a dosage unit of hydrochloride, for example, wherein the kit comprises a) 7 to 14 dosage units containing 0.06 mg fingolimod, b) 7 to 14 containing 0.125 mg fingolimod Dosage unit, c) 7 to 14 dosage units containing 0.250 mg fingolimod, d) 0.375 mg fingolimod, and optionally 0.5 mg fingolimod dosage unit. For example, the kit contains 7 dosage units containing 0.06 mg fingolimod, 7 dosage units containing 0.125 mg fingolimod, 7 dosage units containing 0.25 mg fingolimod and 7 containing 0.375 mg Dosage unit of fingolimod; or 14 dosage units having intensity of each dose.

In one embodiment, the kit may contain only one low dose dosage unit, the dose strength of which corresponds to the starting dose of the S1 P receptor modulator or agonist of the invention. The patient may then take one unit of the low dose of the agent within a specified number of days, and then take two or more units on subsequent days as needed until the start of the use of a standard daily dose of the S1P receptor agonist.

In another embodiment, the kit can comprise a plurality of low dose dosage units having a range of dose strengths such that a dosage unit can be administered to the patient daily, but the S1P receptor modulator administered thereto The amount of the agonist can be titrated until the standard daily dose of therapy is initiated.

For example, the daily unit of the S1P receptor modulator or agonist may be about 1/8 or 1/9 of the standard dose of the S1P receptor modulator or agonist, respectively, about 1/4, about 1/2 and about 1/1.5.

In another embodiment, the daily unit of the S1P receptor modulator or agonist may be about 1/8 of the standard dose of the S1P receptor modulator or agonist, respectively. 1/4 and about 1/2, or about 1/4 and about 1/2.

The kit may further comprise a standard daily dosage unit of a SIP receptor modulator or agonist of the invention, such as fingolimod or its hydrochloride.

This kit can also contain instructions for use.

In another embodiment of the present invention, provided

5.1 A method of assessing a patient's need or suitability for a course of treatment as described above (e.g., in any of the specified aspects or embodiments of the invention), comprising the steps of: (i) determining that the invention will be Whether the patient treated with the S1P receptor modulator or agonist belongs to a class that can benefit from the therapeutic course as described above; and (ii) if the patient falls into this category, the patient is treated with the therapeutic treatment as described above .

5.2 A method as defined in 5.1, in which the patient suffers from or is suspected of heart failure, arrhythmia, high-grade atrial-ventricular obstruction or diseased sinus syndrome or has a history of syncope; or is receiving beta blockers or anti-heart rhythms Irregular drug therapy, for example, when anti-arrhythmia therapy is being used; or maintenance of a dose regimen or treatment leave, such as a vacation of more than 4 days, more than 6, 8, 10, 12 or 14 days, the patient may belong to The above categories.

The course of administration of an S1 P receptor modulator or agonist to an individual in accordance with the present invention may be provided during the onset of the disease therapy, for example during the first 14 days, such as the first month, such as during the first two months. It may also be provided after the termination of the therapy, for example after more than 10 days of termination, more than 12 days, for example more than 14 days.

The utility of the present invention in the treatment of diseases and conditions as described above It can be determined in standard animal or clinical tests, for example, according to the methods described below. For example, the titration value can be determined by verifying any of the following parameters: avoiding a sudden drop in heart rate after treatment initiation, minimizing the risk of AV conduction abnormalities or reducing the sustained magnitude of heart rate decline.

Example:

Two different fingolimod dosing regimens within 30 days of daily dosing: 0.125 mg-0.25 mg-0.5 mg and 0.06 mg-0.125 mg-0.25 mg-0.375 mg-0.5 mg with fixed fingolimod 0.5 mg Comparison of drugs.

A total of 60 individuals were screened and subsequently scheduled into one of four groups (two dosing titration groups, or placebo or positive control group) and received a daily treatment in a blinded manner.

Individuals participated in the screening period of up to 21 days, baseline (1-day) and 30-day active treatment period.

After the last dose, a pharmacokinetic and safety assessment of up to 24 hours was performed. Heart rate (HR) was monitored on the first day before breakfast until 24 hours after the last dose on the 31st day. The heart rate system was evaluated by continuous Holter monitoring on a 1-hour, day 1 and day 29 basis. On day 31, a study was performed to complete the assessment to rule out clinical signs of toxicity or infection, and then the individual was withdrawn from the study.

The average daily HR, and the daily minimum HR and the daily average minimum HR are assessed. The daily average minimum HR is defined as the minimum of the hourly average observed over the day.

In order to assess whether there is any other HR decline between the administration of one dose and the subsequent increase in dose, the last day of the lower dose in each titration population is The minimum and minimum mean HR comparison between the first day of the higher dose. This analysis uses a Bayesian analysis with no information prior.

The hourly average and minimum HR were also measured on days 1, 8, 15, 22 and 29. The mean and +/- standard deviation of the hours after administration of the treatment group and the first 6 hours after administration on days 1, 8, 15, 22, and 29 were plotted.

The following table describes the treatment sequence of the study

result:

Daily Fingolimod 0.5 mg resulted in an average HR drop of about 10 bpm for the 6th hour of Day 1. By day 14 and thereafter, the HR of this treatment group gradually increased. Titration group-1 slowly accumulated a negative chronotropic effect during the first two weeks of the study, approximately 6 to 7 bpm compared to the baseline or placebo group and subsequently stabilized between the second and fourth weeks. Evidence demonstrates that HR is further significantly reduced when the 0.5 mg fingolimod dose is started on day 29. Titration group-2 slowly accumulated a negative chronotropic effect during the first three weeks of the study, approximately 5 bpm compared to the baseline or placebo group, and subsequently stabilized between the third and fourth weeks. In comparison, both titrations reduced HR by 3 to 5 bpm during the first six hours. Therefore, two titrations did reduce the effect of HR on the first 6 hours of the first day of fingolimod treatment compared to the clinical dose of fingolimod.

These results demonstrate that the use of the dosing regimen according to the present invention attenuates the negative chronotropic effects observed on day 1 of the start of fingolimod treatment. In addition, multiple analyses have been performed to compare the minimum heart rate between the two treatment groups. This analysis shows that the fingolimod dosing titration course provides a modified day minimum heart rate during the study period.

In summary, these low fingolimod dose studies can effectively attenuate the negative chronotropic effects of fingolimod treatment at the beginning.

Claims (9)

An S1P receptor modulator or agonist for use in the treatment or prevention of chronic chronic diseases, wherein the S1P receptor modulator or agonist is at least 2 weeks from the start of the treatment, for example within 4 weeks to less than the treatment day The daily dose of the dose is administered, and then the daily dose of the treatment is administered, and wherein the S1P receptor modulator or agonist is in the form of a free form, a phosphate derivative or a 2-amino group in the form of a pharmaceutically acceptable salt - 2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (fingolimod). The S1P receptor modulator or agonist of claim 1, wherein the dose administered is gradually increased in at least one dose increment prior to administration of the therapeutic daily dose, and wherein the same dose is administered continuously for at least one week, for example Two weeks, then increase. An S1P receptor modulator or agonist according to claim 1 or 2, wherein the first dose that is at least 4 times lower than the therapeutic dose, for example, 8 times lower, is administered continuously for at least one week. The S1P receptor modulator or agonist according to any one of claims 1 to 3, wherein prior to administration of the therapeutic dose, the first dose being at least 4 times lower than the therapeutic dose is administered continuously for 2 weeks, followed by two During the week, a second dose that is at least 2 times lower than the therapeutic dose is administered. The S1P receptor modulator or agonist according to any one of the preceding claims, wherein the S1P receptor modulator or agonist is administered continuously at a dose of 0.125 mg per day for 2 weeks and then continuously administered at a dose of 0.25 mg per day. week. The S1P receptor modulator or agonist according to any one of claims 1 to 3, wherein the first dose administered is less than 10 to 8 times the therapeutic dose, wherein The dose is increased at least three times to reach the therapeutic dose, and the same dose is administered continuously for at least one week. The S1 P receptor modulator or agonist according to any one of the preceding claims, wherein the first dose administered is about 0.06 mg per day. The S1P receptor modulator or agonist according to claim 6 or 7, wherein the S1P receptor modulator or agonist is administered continuously at a dose of 0.06 mg per day for the first week to 0.125 mg prior to administration of the therapeutic dose. Continued to vote for the second week, continue to 0.25 mg for the third week and continue to vote for the fourth week with 0.375 mg as needed. The S1P receptor modulator or agonist according to any one of the preceding claims, wherein the therapeutic daily dose is 0.5 mg.