KR20090063228A - Titration schedule for bifeprunox for treating schizophrenia and kits for use therein - Google Patents

Abstract

The present invention is directed to the use of a bifeprunox compound for a titration kit for a titration schedule to facilitate the initiation of the treatment of at least one central nerv ous s ystem condition or disorder by administering a plurality of dosage units of a comprising a compound 7-[4-([1,1'-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone (INN bifeprunox).

Description

 Titration schedule for bifeprunox for treating schizophrenia and kits for use therein}

The present invention relates to compound 7- [4-([1,1'-biphenyl] -3-ylmethyl) -1-piperazinyl] -2 (3H) -benzoxazolone monomethane-sulfonate (INN bipep) The present invention relates to compositions, kits, and methods for titration planning that facilitate the onset of treatment of one or more central nervous system (CNS) conditions or disorders by administering a plurality of dosage units of a composition comprising Lunox).

Compound 7- [4-([1,1'-biphenyl] -3-ylmethyl) -1-piperazinyl] -2 (3H) -benzoxazolone (INN bifefranox) is represented by Formula (I) Have

The hydrochloride of the above-mentioned formula, i.e. (7- [4-([1,1'-biphenyl] -3-ylmethyl) -1-piperazinyl] -2 (3H) -benzoxazolone, is described in WO 97. / 36893 described and claimed, monomethanesulfonate salts are described and claimed in WO 02/066449, which are incorporated herein by reference, and WO 05/16898 is also non-pept. The different polymorphic forms of Lunox mesylate are described and claimed, which are incorporated herein by reference, N-oxides of Bifeprunox are described in WO 2007/023141, incorporated herein by reference. have.

Bifeprunox (known above as DU 127090) binds to the dopamine D ₂ -type receptor and the 5-HT _1A receptor, which is a partial agonist for the dopamine D _2/3 receptor and also to the serotonin 5-HT _1A receptor. Feenstra et al., WO 97/36893; Van Vliet et al., DU 127090: A Highly Potent, Atypical Dopamine Receptor Ligand, 10 (3) Journal of the European College of Neuropsychopharmacology (ECNP) S294 (2000); Feenstra et al., New 1-aryl-4- (Biarylmethylene) piperazines as Potential Atypical Anti-psychotic Agents with Mixed Dopamine D ₂ -Receptor- and Serotonin 5-HT _1A Receptor Affinities, 11 Bioorg.Med.Chem Lett. 2345-2349 (2001); Feenstra et al., New Approaches in Antipsychotics: Design and Synthesis of Ligands Binding to Dopamine-D ₂ and Serotonin 5-HT _1A Receptors, Clinical Candidates DU 127090 and SLV313, Drugs of the Future. 27 (Suppl. A) (2002); Hesselink et al., DU 127090, SLV308 and SLV318: Characterization of a Chemically Related Class of Partial Dopamine Agonists with Varying Degrees of 5-HT _1A Agonism, 10 Eur. J. Neurol. 2151 (2003)).

Bifeprunox affinity for both dopamine D ₂ and serotonin 5-HT _1A receptors makes them useful for the treatment of schizophrenia and other mental disorders. For example, Bifeprunox is an infection or CNS disease (e.g. Parkinson's disease, aggression, anxiety disorder, autism, dizziness, depression, bipolar disorder, cognitive or memory disorder caused by a disorder of the dopamine or serotonergic system). ), And also schizophrenia and other mental disorders.

During clinical studies of bifefranox mesylate, the compounds are well tolerated, but undesirable adverse effects (eg nausea, vomiting and orthostatic hypertension) can occur during the start of treatment, which often results in early discontinuation of the treatment. And / or induce noncompliance of the treatment plan. There is also a need to not only reduce undesirable side effects at the start of treatment, but also to ensure compliance with the treatment plan. This is common in the treatment of patients with CNS disorders, in particular in the treatment of patients with antipsychotics, in order to initiate treatment with a suitable period in which the dose of the drug is gradually increased over a certain period of time. However, the length of the titration period and the dose used, and the increase in dose, are drug-dependent. Therefore, there is a need to find an appropriate titration plan for the safe and effective initiation of treatment with bifefranox. Today, surprisingly, it has been found that resistance to compounds can be improved and the occurrence of one or more undesirable side effects can be reduced or prevented by a gradual increase in the dose of bifeprunox compound according to the titration scheme of the present invention. .

Thus, the present invention relates to compound 7- [4-([1,1'-biphenyl] -3-ylmethyl) -1-piperazinyl] -2 (3H) -benzoxazolone monomethane-sulfonate (INN A composition, kit, and method for a titration plan that facilitates the initiation of treatment of one or more CNS conditions or disorders by administering a plurality of dosage units). For example, the present invention provides for use in a titration plan for titrating a dose of one or more non-peprunox compounds for a period of time up to a maintenance dose for the treatment of one or more central nervous system conditions comprising a plurality of composition unit doses. A composition dosage regimen, wherein each unit dose comprises one or more non-peprunox compounds, the duration of the titration plan includes six or more time segments, and one or more non-pep for the entire titration plan. The dose of lanox compound is increased in concentration at every hour portion.

Also described herein are titration kits, wherein each unit dose comprises at least six consecutive unit doses comprising one or more non-peprunox compounds, wherein the unit dose is increased in concentration over the entire titration period.

In addition, the present invention encompasses administering to a subject a composition regimen comprising a plurality of composition unit doses, wherein each unit dose comprises one or more non-peprunox compounds. A method for titration planning to initiate treatment of a central nervous system condition, wherein a unit dose during an overall titration plan increases the amount of one or more bifeprunox compounds. Finally, one or more side effects associated with initiation of bifeproxnox treatment, comprising administering a composition regimen comprising a plurality of composition unit doses, each unit dose comprising one or more bifeprunox compounds. A method of reducing is described herein, wherein the unit dose for the titration scheme increases the amount of one or more non-peprunox compounds.

Bifeprunox compounds are proposed for the treatment of CNS disorders, including schizophrenia, other psychiatric disorders and Parkinson's disease. In the configuration of the present invention, the dose concentration is expressed in an amount corresponding to the bifeprunox base. As used herein, the term "bipefranox based" refers to compound 7- [4-([1,1'-biphenyl] -3-ylmethyl) -1-piperazinyl]-of the formula: 2 (3H) -benzoxazolone (INN bipefranox).

Typical dosing regimens range from an amount corresponding to 0.05-60 mg of bifefranx substrate; The dose may vary in part based on the severity of the CNS condition and other conditions of the patient.

For example, a titration planned dose or maintenance dose for a bifeprunox compound may be a dose corresponding to a bifeprunox based 10 mg / day, 20 mg / day, 30 mg / day or 40 mg / day. In clinical studies, the efficacy, safety and tolerability profiles of Bifeprunox suggest that this may be an effective agent for use as a treatment option in patients with schizophrenia. Despite the efficacy, safety and tolerability profiles, bifefranox treatments can cause adverse effects during the initiation of treatment, which can lead to discontinuation and / or inconsistent use of treatment.

As used herein, the term "bifefranox compound (s)" refers to the active compound 7- [4-([1,1'-biphenyl] -3-ylmethyl) -1-piperazinyl] -2 (3H) -benzoxazolone, N-oxide and pharmaceutically acceptable salts, solvates and hydrates thereof, and solvates and hydrates of salts. When N-oxide is used as the bifeprunox compound, the amount (mg) is the same amount that the skilled person selects for the bifeprunox compound in the absence of oxide. In addition, pharmaceutically acceptable salts of bifeprunox or its N-oxides can be prepared using standard methods known in the art, for example, by mixing the compounds of the present invention with an appropriate acid, such as an inorganic or organic acid. It can be obtained by.

In an embodiment of the invention, the one or more bifeprunox compounds comprise bifeprunox mesylate. Preferably, the at least one bifeprunox compound is bifeprunox mesylate. Bifeprunox mesylate may be selected from α, β, γ, and δ crystalline polymorph forms, and mixtures thereof. For example, the one or more non-peprunox compounds include one or more polymorph forms selected from α and γ polymorph forms.

The crystalline polymorph form of α bifeprunox mesylate in accordance with the techniques of the present invention, which is the preferred polymorph form, is defined by at least physicochemical parameters as described in WO 2005/016898.

As used herein, the term "titration plan" refers to the dosage regimen of pharmaceutically active agent for a period of time, based in part on the target dose and / or maintenance dose. In one or more embodiments, the target dose and / or maintenance dose is at least 10 mg / day, at least 20 mg / day, at least 30 mg / day, or at least 40 mg / day, for example bifefrux, based on bifeprunox. Doses corresponding to Knox-based 10 mg / day, 20 mg / day, 30 mg / day or 40 mg / day. In particular, the target dose is 20 mg / day of one or more bifefranox compounds. In another embodiment, the target dose is 40 mg / day of one or more bifefranox compounds. For example, the bifeprunox compound administered in the form of multiple unit doses of the composition can be consecutively 6 to 14 days, for example 6 to 10 days and also for example 6 to 8 days, in particular 7 days. It can be made over a period selected from. In addition, the period can be divided into a time portion other than one day, for example, a two or three day portion. In that case, the same unit dose of the bifeprunox compound may be administered within the hourly part of the day, wherein the administration may be not only a dose once a day, but for example half the dose twice a day. The period during which the titration plan continues may exist, in part because of the lowest dose at which titration is initiated, in increments and target doses and / or maintenance doses deemed clinically acceptable; For example, the titration plan can continue over a longer number of days (eg 14 days) and for a shorter period (eg 6 or 7 days). Thus, an aspect of the present invention is a titration plan in which the number of time portions is six or more, and the titration period is 6, 12 or 18 days or more, respectively. Another aspect relates to a titration plan wherein the number of time portions is at least seven and each has a titration period of at least 7, 14 or 21 days. At each unit dose the concentration or amount of the bifeprunox compound is gradually increased over the subsequent titration plan until the target dose and / or maintenance dose is reached. In addition, a continuous concentration or amount of unit dose may be presented such that an overall increase in concentration or amount of unit dose occurs over the entire titration plan during the titration. For example, before the maintenance unit dose is administered, comparing the first unit dose to the last unit dose, there is an increase in the amount of bifeprunox compound administered.

In one embodiment, the unit dose of the composition is about 0.05 to about 0.07 mg, about 0.07 to about 0.18 mg, about 0.18 to about 0.35 mg, about 0.35 to about 0.70 mg, about 0.70 to about 1.4 mg, respectively. , A single concentration dose corresponding to about 1.4 to about 3.5 mg, about 3.5 to about 7.0 mg, about 7 to about 14 mg, and about 14 to about 28 mg. In the case of selecting different concentrations of each unit dose, the concentration may be a subsequent concentration within the group given above.

In another embodiment, the unit dose of the composition is about 0.0550 to about 0.0675 mg, about 0.10 to about 0.15 mg, about 0.20 to about 0.30 mg, about 0.4 to about 0.6 mg, about 0.8 to about 1.2 mg, about 1.5 to about 2.5 mg, about 4.0 to about 6.0 mg, about 8 to about 12 mg, and about 15 to about 25 mg of the bifeprunox compound. In the case of selecting different concentrations of each unit dose, the concentration may be a subsequent concentration within the group given above.

In another embodiment of the titration scheme, the concentration or amount of each unit dose is about 0.0625 mg, about 0.125 mg, about 0.25 to about 0.5 mg, about 1.0 mg, about 2.0 mg, about 5.0 mg, about 10 mg and about 20 It can be selected from a single concentration dose corresponding to mg Bifeprunox substrate.

Within the titration scheme, the unit dose may be increased in the range of about 1.5 to 3 times the previous dose and, for example, in the amount or concentration of the bifeprunox compound that is about 2 to 2.5 times the previous dose. In the case of the initial dose of the titration plan, there is no previous capacity, but there is the remaining capacity of the titration plan, and the previous dose is available for consideration.

The composition usage provided in the art of the invention may be in the form of a kit comprising a plurality of unit doses, for example in the form of tablets, for optimal planning to reach final and / or maintenance doses. The present invention also relates to a titration planning kit for facilitating treatment of one or more central nervous system conditions comprising unit doses of a plurality of compositions comprising one or more non-peprunox compounds, wherein the unit dose over the titration plan Increases the amount of bifeprunox compound. Thus, one aspect relates to a titration kit comprising at least six consecutive unit doses, wherein each unit dose comprises one or more non-peprunox compounds, wherein the unit dose is concentrated over the entire titration period. Is increased. The concentration or amount of each unit dose may be selected from the group of different concentrations given above. In another embodiment, the titration period of the kit is divided into six or more time portions (as defined above).

Kits as described above may be in the form of a package, for example a blister package, wherein the package comprises a plurality of tablets, for example, each tablet has a different capacity than the other tablets, For example, with an indication disposed adjacent to the tablet to indicate a continuous concentration and / or a continuous number of days).

In another embodiment, the kit may be in the form of a package comprising a plurality of capsules, granular aerosols, suppositories and / or suspensions to form each unit dose. Such dosage forms, together with inert, pharmaceutically acceptable excipients, carriers and / or pharmaceutically acceptable ingredients, form polymorphs of the bifeprunox compound (e.g., bifeprunox in α, γ and / or δ). Mesylate) can be prepared separately or by mixing together.

In the preparation of the compositions of the present technology, the active ingredient, i.e., the bifeprunox compound, may be a solid powder ingredient (e.g., lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin) or other suitable ingredients, and It can be mixed with disintegrants and lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture can then be processed into granules and compressed into tablets and / or other known pharmaceutical forms (eg suppositories and / or suspensions).

Soft gelatin capsules may also be prepared that contain a composition comprising the active ingredient, vegetable oil, fat or other suitable soft gelatin capsule vehicle of the present invention. Hard gelatin capsules may contain granules of the active ingredient. Hard gelatin capsules may also contain the active ingredient together with solid powder ingredients (eg, lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin).

In addition, the compositions of the present technology may include one or more pharmaceutical excipients. Non-limiting examples of suitable excipients include suspending agents (e.g. rubber, xanthan, cellulose and sugars), humectants (e.g. sorbitol), solubilizers (e.g. ethanol, water, PEG and propylene glycol), surfactants (e.g. Sodium lauryl sulfate, Spans, Tweens and cetyl pyridine), preservatives, antioxidants (e.g. parabens and vitamins E and C), anti-caking agents, coatings, chelating agents (e.g. EDTA), Stabilizers, antimicrobials, antifungal or antibacterial agents (e.g. parabens, chlorobutanol, phenol, sorbic acid), isotonic agents (e.g. sugars, sodium chloride), thickening agents (e.g. methyl cellulose), flavoring agents (e.g. Chocolate, talmantin, aspartame, root beer or watermelon, other flavors stable at pH 7-9), antifoams (e.g. simethicone, Mylicon®), disintegrants, flow aids, lubricants, adjuvants , Colorants, diluents, wetting agents, preservatives, carriers, binders (e.g., hydroxypropylmethylcellulose, Rivinyl pyrrolidone, other cellulose materials and starches), diluents (e.g. lactose and other sugars, starches, dicalcium phosphate and cellulose materials), disintegrants (e.g. starch polymers and cellulose materials), glidants and water insolubles Or water-soluble lubricants or lubricity agents.

The active ingredient may be premixed separately from other non-active ingredients before mixing to form the formulation. The active ingredients may also be mixed with each other prior to mixing with the non-active ingredients to form a formulation.

When different from the examples or otherwise indicated, all numbers, reaction conditions, and the like, which indicate amounts of ingredients used in the specification and claims, are to be understood as being modified in all instances by the term "about." Thus, unless indicated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending upon the desired properties to be obtained herein. At the very least, and not as an attempt to limit the application of the contents corresponding to the claims, each numerical parameter should be considered in terms of a number of important numerical and commonly performed approaches.

Although the numerical ranges and parameters presented are approximations, the numerical values set forth as specific examples have been reported in as much detail as possible. However, numerical values necessarily include specific errors resulting from the standard deviation found in each of these test measurements. As a result of the following examples, the present invention will be described without restricting the scope.

Example 1 Materials and Methods

The alpha polymorphic form of bifeprunox mesylate is prepared as described in WO2005 / 16898. Sodium starch glycolate, sodium stearyl fumarate, microcrystalline cellulose and lactose monohydrate are commonly used in pharmaceutical grades from commercially available sources.

Example 2: Preparation of 10 mg Tablets

Tablets with a concentration of 10 mg are prepared according to the following method (the amounts required for all concentrations are shown in the table below).

Microcrystalline cellulose is added to bin blender A and mixed for 5 minutes to dispense. Transfer water to empty Mixer B and mix for 5 minutes to dispense. The following ingredients are added to empty mixer B and mixed for 25 to 35 minutes; Lactose Monohydrate Bifeprunox mesylate 1/2 part, Sodium Starch Glycolate and Lactose Monohydrate remaining 1/2.

Granulation is milled / de-aggregated by a rotary impeller-screening mill using a conical sieve equipped with a 0.6 mm sieve or 0.8 mm sieve. Transfer the granules to empty mixer A. To empty mixer A, sodium stearyl fumarate and colloidal silicon dioxide (only 20 mg only) are added and sieved through # 20 mesh. The granules are mixed at 6-8 rpm for a goal of 10-25 minutes.

The granules are compressed in a rotary tablet press and collected in a suitable container.

Core tablets are loaded into perforated coated pans. Sufficient Opadry II film coating suspension is added to obtain a core weight of about 3.5%. Do not load tablets into appropriate containers.

Tablets with concentrations of 0.25 mg / tablet, 0.5 mg / tablet, 1.0 mg / tablet, 2.0 mg / tablet, 5.0 mg / tablet and 20 mg / tablet are lactose monohydrate and / or microcrystalline to meet the same final weight. It should be understood that while supplementing with the amount of cellulose is prepared in a corresponding manner by reducing or increasing the amount of bifeprunox mesylate, different coating components are used to obtain different colors for all tablet concentrations (see Table 1 ).

Example 3: Clinical Study

This study represents a randomized, double-blind, placebo-regulated, continuous panel, rapid titration study of the safety and tolerability of bifefranox compounds in individuals with schizophrenia. In particular, this study evaluates safety, tolerability and efficacy after rapid titration of Bifeprunox to a 40 mg / day therapeutic dose to schizophrenia and schizophrenic individuals. Appropriate subjects are admitted at the beginning of the screening period and introduced into a single-blind placebo run-in period (-7 to -1 days) to antipsychotic agents on day 7 prior to the bifeproxox titration. Ensure that the member reaches the range. The subject is then started with a rapid titration at an initial bipeduloxin starting dose of 0.25 mg, using a highly suggested therapeutic dose of 40 mg / day. The two titration plans are evaluated in a sequential order and the titration period lasts 6 to 7 days according to the titration plan (day 1 to 6 or 7).

The doses presented in the titration plan, respectively, are administered once daily (QD), followed by higher doses the following day. If the subject is not tolerant of the dose given, the subject should be repeated on the same dose, especially for one day, before increasing the dose to the next level. However, only one repeat dose is allowed for the entire titration period. At the high suggested dose of 40 mg / day, subjects are given a 3-day maintenance period for this dose. The final assessment is performed on the day after the last maintenance period dose, and the follow-up assessment is performed 3 days after the last dose of study treatment.

Efficacy assessments (ie positive and negative symptoms of schizophrenia (PANSS) and Clinical Global Impression-Severity (CGI-S) perform CGI-I (Clinical Global Impression-Improvement) on day 1 at screening and final evaluation) Only perform at final evaluation. Safety was assessed by physical examination, vital signs, adverse effects (AEs), concomitant medications, clinical laboratory assessments, 12-cardiogram (ECGs), Simpson-Angus Scale (SAS) scores, and the Vans Arcaticia Scale ( Monitor through the study by evaluation of the BAS (Barnes Akathisia Scale) score. The treatment phase lasts approximately 2 weeks, including review assessment. Subjects remain hospitalized until post-treatment review evaluation is complete or until their condition is clinically stabilized.

The study plans to include 20 individuals (10 individuals per panel). 27 individuals are screened and 18 randomized (7 for Bifeprunox in titration plan 1 and 1 for placebo, 8 for Bifeprunox in titration plan 2c and 2 for placebo ). Ten individuals per panel are used as initially planned. However, two individuals were excluded from the first panel before the start of the study. In addition, the study is conducted on 18 individuals.

Men and women aged 18 to 55 years are diagnosed with the Diagnostic and Statistical Manual of Mental Disorders, 4 ^th of schizophrenia disorders (295.10, 295.20, 295.30, 295.60, and 295.90) or schizophrenic disorders (295.70). edition, Text Revised (DSM-IV TR) diagnosis.

Bifeprunox is an orally administered tablet with a total daily dose of 0.25-40 mg according to the following titration scheme:

Placebo tablets corresponding to non-peprunox tablets are administered orally using the same dosage regimen as the test product is administered.

Efficacy Results: Due to the short duration of the treatment period used in this study, improving responder rates based on the schizophrenia symptoms and the PANSS total score as measured by the PANSS total score, CGI-S and CGI-I scores There are very few benefits of bifefranox treatment for placebo.

Safety Results: The transient pattern of intolerability observed during titration plan 1 leads the investigator to suggest a less aggressive titration plan for the second panel of subjects. Other titration schemes, 2a, 2b and 2d (jumping to doses of 0.25 mg to 2 mg to 10 mg, and 0.25 mg to 1 mg, respectively), are not optimal based on tolerance data. Therefore, titration plan 2c, a longer and more conservative titration plan, is selected for the second panel of individuals. The selection of titration plan 2c was shown to reduce the AE observed during titration plan 1, which was a more gradual increase to 0.25-10 mg and then 40 mg dose using 7-day rather than 6-day titration plan. It shows the advantages according to.

In Titration Scheme 1, all individuals in the non-peprunox group reported at least one treatment of emergent adverse event (TEAE). Adverse effects are mostly reported at 0.25 to 10 mg dose levels, particularly at 5 mg doses. The most commonly observed TEAEs are neurological disorders (sleepiness, dizziness, headache NOS and ambulatory NOS) and gastrointestinal disorders (nausea and vomiting). However, orthostatic hypotension was also reported at the 1, 5, 10 and 40 mg dose levels. TEAE does not occur at the 20 mg dose level. All individuals who received bifefranox in titration plan 1 are considered to have one or more TEAEs involved in study treatment, and all TEAEs occurring in the nervous system are considered to be involved in study treatment. Three subjects who received bifefranox in titration plan 1 reported TEAEs that were considered severe, and most commonly reported cases occurred in the nervous system. Severe TEAE of orthostatic hypotension, nausea, vomiting NOS and stiffness has been reported. All severe TEAEs occur at 1, 5 and 10 mg dose levels.

Two individuals who received bifefranox in titration plan 1 had more than one vital sign on the same day as the associated AE (dizziness or orthostatic hypotension). Changes in blood pressure and heart rate are associated with TEAEs of dizziness and orthostatic hypotension leading to re-challenge and / or discontinuation of the subject's dose levels from the study, and headache BOS, nausea and drowsiness TEAEs are also associated with re-challenge and / or discontinuation. Usually relevant. Three individuals (one of them male and two female) experience TEAEs leading to discontinuation of study treatment, all individuals report TEAE associated with study treatment, and two of three individuals Re-challenge is required. Re-challenge was successful for all of these individuals performing titrations at higher doses, but they were actually stopped due to additional TEAEs.

In titration plan 2c, all individuals in the non-peprunox group reported at least one TEAE. Although little adverse effects were reported at the 10 mg dose, adverse effects were reported at all dose levels. More AEs were reported at the 40 mg dose level in titration plan 2c when titrating below 40 mg dose to more patients than in titration plan 1. The most commonly observed TEAEs are neurological disorders (dizziness, headache NOS and sleepiness) and gastrointestinal disorders (digestion and nausea). Six of the eight individuals who received bifefranox in titration plan 2c are believed to have TEAEs associated with the study treatment, the most commonly reported case occurring in the nervous system. In contrast to Titration Plan 1, fewer cases of sleepiness that were thought to be related to study treatment were reported in fewer subjects, and no TEAEs of anorexia, ambulatory NOS or orthostatic hypotension were reported. Three individuals who received bifefranox in titration plan 2c reported TEAEs considered to be severe. All three individuals reported severe TEAE of dizziness and severe TEAE of paleness in one subject. All severe TEAEs occur at the 2 mg and 5 mg dose levels. One subject receiving placebo in titration plan 2c reported severe adverse effects (SAEs) (facial injuries).

Four individuals who received bifefranox in titration plan 2c had more than vital signs on the same day as the AE of dizziness. Changes in blood pressure and heart rate are associated with dizziness TEAEs that lead to re-challenge and / or discontinuation of an individual's dose level from the study. One female subject experiences dizziness TEAE (associated with study treatment) that induces discontinuation of study treatment and requires a dose level re-challenge. In addition two individuals will need a dose level of rechallenge, followed by completion of the titration plan up to a maximum dose of 40 mg. However, overall, more individuals with vital signs abnormalities (such as AE and significant adverse outcomes) in titration plan 2c complete the titration up to the 40 mg dose level than in titration plan 1.

Bifeprunox's titration plan has been shown to have no effect on BAS, SAS, ECG or clinical laboratory evaluation. None of the changes observed on the physical examination are judged to be clinically meaningful in each plan.

In titration plan 1, subjects are administered bifeprunox for six consecutive days at doses of 0.25, 1, 5, 10, 20 and 40 mg. In this titration scheme, most AEs occur in the 0.25 to 10 mg dose range. At the 10 mg dose, resistance to a daily increase from 20 to 40 mg is excellent. Titration Scheme 2c is a slower titration up to the 10 mg level, administered to the subject for seven consecutive days with 0.25, 0.5, 2, 5, 10, 20 and 40 mg bipefranox. This longer and more conservative titration plan results in lower avoidance from studies due to intolerance effects, and has been shown to reduce the AE observed during titration plan 1. Exposure is comparable between the two schemes for metabolites, while non-peprunox exposure is approximately 1.3 to 1.5 times higher in titration scheme 2c than titration scheme 1 on the last study day. The results of this study generally indicate that a Bifeprunox titration of 0.25-40 mg over 7 days is more resistant than a titration over 6 days. However, it should be noted that the final maintenance dose of this study is 40 mg and the titration plan, ie 6-7 days, is based in part on this last maintenance dose level.

Claims (21)

Ratios for the preparation of the composition regimen for doses of one or more bifeprunox compounds for a period of time up to a maintenance dose for the treatment of one or more central nervous system conditions, comprising a plurality of unit doses of one or more bifeprunox compounds. A titration plan for titrating the use of a peprunox compound and a unit dose containing one or more non-peprunox compounds, wherein the duration of the titration plan is divided into six or more time segments, The dose of one or more non-peprunox compounds across is increased in concentration at each hour portion). The use according to claim 1, wherein the number of time portions is seven or more times. The use according to claim 1 or 2, wherein the time portion is one day, two days or three days. The method of claim 1, wherein the unit dose is about 0.05 to about 0.07 mg, about 0.07 to about 0.18 mg, about 0.18 to about 0.35 mg, about 0.35 to about 0.70 mg, about 0.70 to about 1.4 Use is selected from single concentration doses ranging from mg, about 1.4 to about 3.5 mg, about 3.5 to about 7.0 mg, about 7.0 to about 14.0 mg and about 14.0 to about 28.0 mg. The method of claim 4, wherein the unit dose is about 0.0550 to about 0.0675 mg, about 0.10 to about 0.15 mg, about 0.20 to about 0.30 mg, about 0.4 to about 0.6 mg, about 0.8 to about 1.2 mg, about 1.5 to about 2.5 mg. , About 4.0 to about 6.0 mg, about 8.0 to about 12.0 mg, and about 15.0 to about 25.0 mg. 6. Use according to claim 5, wherein the unit dose is selected from single concentration doses of 0.0625 mg, 0.125 mg, 0.25 mg, 0.5 mg, 1.0 mg, 2.0 mg, 5.0 mg, 10 mg and 20 mg. The method according to any one of claims 1 to 6, wherein the concentration of the unit dose of bifepronox at the next time portion is determined after About 1.5 to 3 times the concentration of the unit dose of the preceding time portion. The use according to any one of claims 1 to 7, wherein the maintenance dose is at least 20 mg / day of at least one non-peprunox compound. The use according to any one of claims 1 to 8, wherein the bifeprunox compound is bifeprunox mesylate. 10. The use according to claim 9, wherein the bifeprunox compound is an alpha polymorph of bifeprunox mesylate. A titration kit comprising at least six consecutive unit doses, wherein each unit dose comprises one or more non-peprunox compounds, wherein the unit dose is increased in concentration over the entire titration period. The kit of claim 11, wherein the kit comprises at least seven unit doses with increased concentrations of the at least one non-peprunox compound. The kit of claim 11 or 12, wherein the titration period is divided into six or more time parts. The kit of claim 13, wherein the time portion is 1 day, 2 days or 3 days and comprises a plurality of unit doses of the same concentration for each time portion. The method of claim 11, wherein the unit dose is about 0.05 to about 0.07 mg, about 0.07 to about 0.18 mg, about 0.18 to about 0.35 mg, about 0.35 to about 0.70 mg, about 0.70 to about 1.4 Kit selected from single concentration doses of mg, about 1.4 to about 3.5 mg, about 3.5 to about 7.0 mg, about 7.0 to about 14.0 mg, and about 14.0 to about 28.0 mg. The method of claim 15, wherein the unit dose is about 0.0550 to about 0.0675 mg, about 0.10 to about 0.15 mg, about 0.20 to about 0.30 mg, about 0.4 to about 0.6 mg, about 0.8 to about 1.2 mg, about 1.5 to about 2.5 mg. And a single concentration dose of about 4.0 to about 6.0 mg, about 8.0 to about 12.0 mg, and about 15.0 to about 25.0 mg. The kit of claim 16 wherein the unit dose is selected from single concentration doses of 0.0625 mg, 0.125 mg, 0.25 mg, 0.5 mg, 1.0 mg, 2.0 mg, 5.0 mg, 10 mg and 20 mg. 18. The kit of any one of claims 11 to 17, wherein the amount of increase in the concentration of the unit dose of bifeprunox at a particular concentration ranges from about 1.5 to 3 times the previous concentration. 19. The kit of claim 18, wherein the amount of increase in concentration of the unit dose of bifeprunox at a particular concentration ranges from about 2 to 2.5 times the previous concentration. 20. The kit of any one of claims 11-19, wherein the bifeprunox compound is bifeprunox mesylate. The kit of claim 20, wherein the bifeprunox compound is an alpha polymorph of bifeprunox mesylate.