WO2010070061A1

WO2010070061A1 - Compositions, kits and methods of a titration schedule for bifeprunox compounds

Info

Publication number: WO2010070061A1
Application number: PCT/EP2009/067440
Authority: WO
Inventors: Antje A. Winsemius; Dorte Malling
Original assignee: Abbott Healthcare Products B.V.; H. Lundbeck A/S
Priority date: 2008-12-19
Filing date: 2009-12-17
Publication date: 2010-06-24

Abstract

The present invention is directed to the use of at least one bifeprunox compound for the manufacture of a composition regimen of incrementally increasing dosages of the at least one bifeprunox compound to be used for titration over a period of time up to a maintenance dosage for the treatment of at least one central nervous system condition, comprising a plurality of unit dosages of the at least one bifeprunox compound, wherein the titration takes place over 20 to 28 days and the dosage of the at least one bifeprunox compound over the entire titration schedule increases incrementally to reach a maintenance dosage of 20 mg/day. The composition regimen of the invention is useful for reducing at least one side effect selected from nausea and vomiting associated with the initiation of a bifeprunox treatment.

Description

COMPOSITIONS, KITS AND METHODS OF A TITRATION SCHEDULE FOR BIFEPRUNOX COMPOUNDS

The present invention relates to compositions, kits, and methods for a titration schedule to facilitate the initiation of the treatment of at least one central nervous system (CNS) condition or disorder by administering a plurality of dosage units of a composition comprising a compound 7-[4-([1 ,1 '-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)- benzoxazolone monomethane-sulfonate (INN bifeprunox).

The compound 7-[4-([1 ,1 '-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone has the following formula:

The hydrochloric acid salt of the above-referenced compound is described and claimed in WO 97/36893 and the monomethanesulfonate salt is described and claimed in WO 02/066449, which are incorporated herein by reference. In addition, WO 05/016898 describes and claims the different polymorphic forms of bifeprunox mesylate, which is incorporated herein by reference. The N-oxide of bifeprunox is described in WO 2007/023141 , which is incorporated herein by reference. In the framework of the present invention these compounds are indicated as "bifeprunox compounds", including pharmaceutically acceptable salts, solvates and hydrates thereof and solvates and hydrates of the salts.

Bifeprunox (earlier known as DU 127090) binds to dopamine D₂ receptors and 5-HT_1A receptors; it is a partial agonist at dopamine D₂/3 receptors and also a partial agonist at serotonin 5-HT_1A receptors. See, e.g., WO 97/36893; Van Vliet et al., 10(3) Journal of the European College of Neuropsychopharmacology (ECNP) S294 (2000); Feenstra et al., 1 1 Bioorg. Med. Chem. Lett. 2345-2349 (2001 ); Feenstra et al., Drugs of the Future 27 (Suppl. A) (2002); Hesselink et al., 10 Eur. J. Neurol. 2151 (2003). Bifeprunox's affinity for both the dopamine D₂ and serotonin 5-HT_1A receptors indicates that it may considered to be useful for the treatment of schizophrenia and other psychotic disorders. For example, bifeprunox can be of value for the treatment of affections or diseases of the CNS caused by disturbances in either the dopamine or serotonergic systems, such as Parkinson's disease, aggression, anxiety disorders, autism, vertigo, depression, bipolar disorder, disturbances of cognition or memory, and further for example, schizophrenia and other psychotic disorders. During clinical investigations on bifeprunox mesylate, the compound was well tolerated, however, adverse events such as, in particular, nausea and vomiting can occur during the initiation of treatment, which may in some instances lead to early discontinuation of the treatment and/or noncompliance with the treatment plan. As such, there is a need to not only reduce the incidence of these adverse side effects at the initiation of treatment, but also ensure compliance with the treatment plan. It is not uncommon in the treatment of patients with CNS disorders, in particular in the treatment with antipsychotics, to start treatment with a titration period in which the dosage of the drug is gradually increased over a specified period of time. The length of the titration period and the dosages used and the increments thereof are, however, drug- dependent. In WO 2008/025780, specifically 6 and 7-day titration regimens for bifeprunox are disclosed. However, there is still a need for an improved titration schedule for safe and effective initiation of the treatment with bifeprunox (including a low discontinuation rate) as nausea and/or vomiting are the main treatment emergent adverse events cited as reason for withdrawal, i.e. stop treatment with the drug, in the titration with bifeprunox. It has now been found that the tolerability to the compound can be improved and in particular the occurrence of nausea and vomiting can be significantly reduced by gradual increase of the bifeprunox compound dose according to the slow titration schedule of this invention. In a comparative study in healthy subjects of 14 days and 25 days of titration it was shown that the incidence of nausea and/or vomiting significantly decrease in the longer titration. Accordingly, the present invention is directed to compositions, kits, and methods for a titration schedule to facilitate the initiation of the treatment of at least one CNS condition or disorder by administering a plurality of dosage units comprising bifeprunox, and in particular the compound 7-[4-([1 ,1 '-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)- benzoxazolone monomethane sulfonate, wherein the titration takes place over a period of 20 to 28 days (Ae. 20, 21 , 22, 23, 24, 25, 26, 27 or 28 days). In particular, the present invention relates to a composition regimen of incrementally increasing dosages of the at least one bifeprunox compound to be used for titration over a period of time up to a maintenance dosage for the treatment of at least one central nervous system condition, comprising a plurality of unit dosages of the at least one bifeprunox compound, wherein the titration takes place over 20 to 28 days and the dosage of the at least one bifeprunox compound over the entire titration schedule increases incrementally to reach a maintenance dosage of 20 mg/day. Further disclosed herein is a titration kit, comprising 20 to 28 unit dosages, each of the unit dosages comprising at least one bifeprunox compound, wherein the dosage of the at least one bifeprunox compound increases in strength over the entire titration regimen. In addition, the present invention is related to a method for a titration schedule for initiating the treatment of at least one central nervous system condition in a subject in need thereof (e.g. a patient) comprising administering to the subject a composition regimen comprising incrementally increasing dosages of the at least one bifeprunox compound to be used for titration over a period of time up to a maintenance dosage for the treatment of at least one central nervous system condition, comprising a plurality of unit dosages of the at least one bifeprunox compound, wherein the titration takes place over 20 to 28 days and the dosage of the at least one bifeprunox compound over the entire titration schedule increases incrementally to reach a maintenance dosage of 20 mg/day.

Further, another embodiment herein is a method for reducing at least one side effect selected from nausea and vomiting associated with the initiation of a bifeprunox treatment comprising administering a composition regimen comprising incrementally increasing dosages of the at least one bifeprunox compound to be used for titration over a period of time up to a maintenance dosage for the treatment of at least one central nervous system condition, the composition regimen comprising a plurality of unit dosages of the at least one bifeprunox compound, wherein the titration takes place over 20 to 28 days and the dosage of the at least one bifeprunox compound over the entire titration schedule increases incrementally to reach a maintenance dosage of 20 mg/day. The composition regimen is particularly suitable for the initiation of treatment with bifeprunox of patients in a maintenance phase of schizophrenia, for whom a change in antipsychotic treatment is decided since they are partially responding to their current treatment or suffering from side effects of the current treatment; in such a "cross- titration", the current antipsychotic medication of the patient will be down-tapered over a fixed number of days, in particular 21 days - so that the last dose is taken on day 21. Bifeprunox will be up-titrated over the same fixed number of days, in particular 21 days, to reach the target maintenance dosage of 20 mg (preferably once daily). In particular, it is an advantage from a tolerability viewpoint (i.e. with regard to high early discontinuation rates due to nausea and/or vomiting) to implement a cross-tapering dosage regimen (cross-titration) when switching from an antipsychotic, in particular a D2 antagonist antipsychotic such as risperidone, to bifeprunox. Preferably, a washout period (wherein a patient is fully downregulated from previous medication) before starting bifeprunox treatment should be avoided.

In the framework of the present invention dosage strength of a bifeprunox compound is expressed in an amount equivalent to bifeprunox base. As used herein, the term "bifeprunox base" refers to the compound 7-[4-([1 ,1 '-biphenyl]-3-ylmethyl)-1-piperazinyl]- 2(3H)-benzoxa-zolone (vide supra, formula I). Accordingly, a maintenance dosage for bifeprunox compounds is a dosage equivalent to 20 mg/day of bifeprunox base. When the N-oxide is used as the bifeprunox compound, the amount in milligrams is the same amount as the amount the person skilled in the art would select for the bifeprunox compound without the oxide. In an embodiment of the present disclosure, the at least one bifeprunox compound comprises bifeprunox mesylate. Preferably, the at least one bifeprunox compound is bifeprunox mesylate. The bifeprunox mesylate may be chosen from the α, v, or δ crystalline polymorphic forms, and mixtures thereof. For example, the at least one bifeprunox compound comprises at least one polymorphic form chosen from the α and v polymorphic forms. Preferably, the crystalline polymorphic form α of bifeprunox mesylate is used which is defined by at least the physicochemical parameters as disclosed in WO 2005/016898.

As used herein, the term "titration schedule" refers to a regimen of dosages of a pharmaceutically active agent to be administered over a restricted period of time to a patient in need thereof, wherein the starting dosage is low and the dosage increases over the restricted period of time to reach a "maintenance dosage". In particular, the maintenance dosage is 20 mg/day of at least one bifeprunox compound. For example, the bifeprunox compound administered in the form of a plurality of unit dosages of a composition can be over the course of a period chosen from 20 to 28 consecutive days, wherein the dosage increases every day to finally reach the maintenance dosage. Alternatively, the titration regimen or composition regimen of the invention can be divided into sets of two, three or four unit dosages (wherein a unit dosage is a separate pharmaceutical composition: e.g. a pill, tablet, capsule) of the at least one bifeprunox compound, each set comprising the same dosage strength of the at least one bifeprunox compound. In that case, the same unit dosage of bifeprunox compound can be administered every day within a certain time segment comprising two, three or four days, wherein the administration may be once daily the full dosage, but also, for example, twice daily half of the dosage. In a specific embodiment of this invention, the composition regimen comprises sets of three unit dosages of the at least one bifeprunox compound comprising the same dosage strength of the at least one bifeprunox compound to be administered over time segments of three days each segment. A further embodiment is a composition regimen to be used in a titration of bifeprunox according to this invention wherein the titration takes place over 21 days. According to an embodiment of this invention, the starting dosage of the at least one bifeprunox compound ranges from about 0.05 mg to about 0.15 mg.

In a further embodiment, each of the unit dosages of the composition are chosen from single strength doses equivalent to bifeprunox base from about 0.05 mg to about 0.07 mg, from about 0.07 mg to about 0.18 mg, from about 0.18 mg to about 0.35 mg, from about 0.35 mg to about 0.70 mg, from about 0.70 mg to about 1.4 mg, from about 1.4 mg to about 3.5 mg, from about 3.5 mg to about 7.0 mg, from about 7 mg to about 14 mg, and from about 14 mg to about 20 mg. When choosing the different strengths of each unit dosage, the strength can be subsequent strengths within the series of sets of dosage units indicated above. In a further embodiment, each of the unit dosages of the compositions are chosen from about 0.0550 mg to about 0.0675 mg, from about 0.10 mg to about 0.15 mg, from about 0.20 mg to about 0.30 mg, from about 0.4 mg to about 0.6 mg, from about 0.8 mg to about 1.2 mg, from about 1.5 mg to about 2.5 mg, from about 4.0 mg to about 6.0 mg, from about 8 mg to about 12 mg, and from about 15 mg to about 20 mg of a bifeprunox compound. When choosing the different strengths of each unit dosage, the strength can be subsequent strengths within the series of sets of dosage units indicated above. In yet a further embodiment of the titration schedule, the strength or amount of each unit dosage may be chosen from single strength doses equivalent to bifeprunox base about 0.0625 mg, 0.125 mg, about 0.25 mg, about 0.5 mg, about 1.0 mg, about 2.0 mg, about 5.0 mg, about 10 mg and about 20 mg. Within the titration schedule divided into sets of two, three or four unit dosages, the unit dosages following the starting dosage may increase in an amount or strength of the bifeprunox compound ranging from about 1.5 to 3 times that of the preceding dosage and further for example, from about 2 to 2.5 times that of the preceding dosage. A specific embodiment of this invention is a composition regimen, kit, or method of treatment wherein the titration takes place over 21 days, wherein the composition regimen comprises seven sets of three unit dosages of the at least one bifeprunox compound, each set comprising unit dosages of the same dosage strength of the at least one bifeprunox compound, starting at a dosage strength of 0.125 mg followed by consecutive strengths of 0.25 mg, 0.5 mg, 1.0 mg, 2.0 mg, 5.0 mg and 10 mg and wherein at day 22 the maintenance dosage is reached. This embodiment is particularly useful in the situation of cross-tapering from current antipsychotic medication, wherein the current antipsychotic medication is down-tapered over 21 days (last dose is taken on Day 21 ), whereas bifeprunox is up-titrated using said composition regimen, kit or method.

A further specific embodiment of this invention is a composition regimen, kit, or method of treatment wherein the titration takes place over 28 days, wherein the composition regimen comprises seven sets of four unit dosages of the at least one bifeprunox compound, each set comprising unit dosages of the same dosage strength of the at least one bifeprunox compound, starting at a dosage strength of 0.125 mg followed by consecutive strengths of 0.25 mg, 0.5 mg, 1.0 mg, 2.0 mg, 5.0 mg and 10 mg and wherein at day 29 the maintenance dosage is reached. This embodiment is particularly useful in the situation of starting the treatment of patients not currently treated with antipsychotic medication. The composition regimen can be in the form of a kit, as described above, which can be in the form of a package, such as a blister package, the package comprising a plurality of tablets, e.g., each tablet having a different dosage than another tablet and further for example, having indicia disposed adjacent to the tablets for displaying successive strengths and/or successive days. In further embodiments, the kit can be in the form a package comprising a plurality of capsules, granular aerosols, suppositories and/or suspensions to form each unit dosage. Such dosage forms can be prepared by mixing, individually or together, the polymorphic forms of the bifeprunox compound (e.g., α, γ and/or δ of bifeprunox mesylate) with inert pharmaceutically acceptable excipients, carriers and/or pharmaceutically acceptable ingredients.

In the preparation of the compositions of the present disclosure, the active ingredients, i.e., a bifeprunox compound, may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules, pressed into tablets, and/or any other known pharmaceutical form such as suppositories and/or suspensions.

Soft gelatin capsules may further be prepared containing a composition comprising a mixture of the active ingredients of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Hard gelatin capsules may contain granules of the active ingredients. Hard gelatin capsules may also contain the active ingredients in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. In addition, compositions of the present disclosure can comprise at least one pharmaceutical excipient. Non-limiting examples of suitable excipients include suspending agents (for example, gums, xanthans, cellulosics and sugars), humectants (for example, sorbitol), solubilizers (for example, ethanol, water, PEG and propylene glycol), surfactants (for example, sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine), preservatives, antioxidants (for example, parabens, and vitamins E and C), anti-caking agents, coating agents, chelating agents (for example, EDTA), stabilizers, antimicrobial agents, antifungal or antibacterial agents (for example, parabens, chlorobutanol, phenol, sorbic acid), isotonic agents (for example, sugar, sodium chloride), thickening agents (for example, methyl cellulose), flavoring agents (for example, chocolate, thalmantin, aspartame, root beer or watermelon or other flavorings stable at pH 7 to 9), anti-foaming agents (e.g., simethicone, Mylicon^®), disintegrants, flow aids, lubricants, adjuvants, colorants, diluents, moistening agents, preservatives, carriers, binders (for example, hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (for example, lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (for example, starch polymers and cellulosic materials), glidants and water insoluble or water soluble lubricants or lubricating agents. The active ingredients may be separately premixed with the other non-active ingredients, before being mixed to form a formulation. The active ingredients may also be mixed with each other, before being mixed with the non-active ingredients to form a formulation. Other than in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained herein. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

The following examples are intended to illustrate the invention without limiting the scope as a result.

EXAMPLES

EXAMPLE 1 : MATERIALS AND METHODS

The alpha polymorphic form of bifeprunox mesylate was prepared as described in WO2005/016898. Sodium starch glycolate, sodium stearyl fumarate, microcrystalline cellulose and lactose monohydrate were used in pharmaceutical grades available from common commercial sources. Encapsulated tablets of different strengths (0.0625, 0.125, 0.25, 0, 5, 1 , 2, 5, 10, 20mg) were prepared according to procedures e.g. as described in WO 2008/025780.

EXAMPLE 2: CLINICAL STUDY

A 3-PART, RANDOMIZED, MULTIPLE-DOSE, SEQUENTIAL DESIGN STUDY OF BIFEPRUNOX IN HEALTHY SUBJECTS IN ORDER TO ESTABLISH A TITRATION REGIMEN WITH AN IMPROVED TOLERABILITY PROFILE Objectives: The primary objective of the study was to evaluate different titration regimens in order to yield an acceptable level of adverse events (AEs) while achieving a total daily dose of 20 mg of bifeprunox in healthy subjects.

The secondary objective of the study was to obtain additional safety and tolerability data about bifeprunox in healthy subjects.

Methodology: This was a 3-part, randomized, inpatient, sequential-group study of multiple oral doses of bifeprunox administered to healthy subjects at 1 investigational site. The sponsor was unblinded to treatment throughout the study, while the study personnel and study participants were blinded. Part 1 determined the feasibility of reaching a 20-mg daily dose in up to 25 days with the target AE profile. The goal of part 2 was to focus on optimizing the 14-day titration regimen while maintaining the target AE profile and the goal of part 3 was to confirm the estimate for the proportion of AE rates in subjects receiving bifeprunox and placebo. For study progression (parts 1 and 2), treatment was deemed unacceptable if a lower bound of the 2-sided exact 90% confidence interval ([CI] equivalent to a 1 -sided 95% Cl) for nausea and vomiting rates was greater than 11 % and 9%, respectively. An acceptable profile was based on the overall tolerability results.

Parts 1 , 2, and 3 were to be conducted and assessed sequentially. The study was not to proceed to the next part until the safety and tolerability of the preceding treatment regimens were evaluated to determine if treatment groups were acceptable. If none of the treatments in part 1 were deemed acceptable, the study was to be completed. In parts 2 and 3, the decision to administer a particular treatment regimen was to be based on the outcome of the preceding part. This was to be conducted in a progressive manner with a confirmatory phase in part 3. Final decisions about selecting treatment regimens during study progression were to be based on the overall clinical tolerability profile. For situations in which more than 1 treatment regimen appeared acceptable, the sponsor was to determine the treatment regimen(s) to take forward. Because the study progression criteria were not met to continue after part 1 , methods and results for parts 2 and 3 are not described further. Number of Subjects: The number of subjects enrolled in this study and who received at least 1 dose of the test article (ie, safety population) was 56: 24 (42.85%) subjects in the 14-day cohort, 26 (46.42%) subjects in the 25-day cohort, and 6 (10.71%) subjects in the placebo cohort. Of the 56 (100%) subjects in the safety population, 52 (92.9%) subjects completed the study.

Four (4, 7.1%) subjects were withdrawn from the study at subject's request, including 1 subject from the 25-day cohort who requested to withdraw from the study after the discovery of pregnancy.

Diagnosis and Main Criteria for Inclusion: The study population consisted of healthy men and nonlactating and nonpregnant women, aged 18 to 50 years, inclusive, with a body mass index (BMI) between 18.0 and 30.0 kg/m2. Women of nonchildbearing potential had to be either surgically sterile or postmenopausal for ≥1 year. Women of childbearing potential had to agree and commit to using an acceptable method of contraception for a period of at least 1 month before the first dose of test article administration, and after the last dose of test article administration.

Test Product, Dose and Mode and Regimen of Administration: All subjects received test article once in the morning on dose administration days and were given their dose at the same time as on day 1 (approximately 0800 hours). All active treatment groups had their bifeprunox dose titrated to 20 mg; subjects received this dose for 3 days. Study drug supplied as encapsulated tablets were available in 0.0625 mg, 0.125 mg, 0.25 mg,

0.50 mg, 1 mg, 2 mg, 5 mg, 10 mg, and 20 mg, respectively.

The treatment regimen for part 1 is presented in Table 1-1. Subjects were randomly assigned to1 of 2 active treatment groups or placebo. The 2 active treatment groups received a starting dose of 0.0625 mg. The 14-day group refers to the treatment group whose 20-mg dose was reached on day 14 and the 25-day group refers to the treatment group which reached the 20-mg dose on day 25. In part 1 , the duration of dose administration was 27 days. Subjects assigned to the14-day titration received placebo beginning with day 17 through day 27.

Table 1 -1 : Part 1 , Treatment Groups and Test Article Administration

Abbreviations: BIF=bifeprunox; PBO=placebo.

Duration of Treatment: It was estimated that the clinical portion of the entire study

(parts 1 to 3) would be completed in approximately 8 months. In part 1 , each subject participated in the study for up to 7 weeks, which included a screening evaluation within

3 weeks before test article administration and a 29-day/28-night inpatient period.

Reference Therapy, Dose and Mode of Administration: Placebo was given as encapsulated tablets.

Criteria for Evaluation: Assessments were performed according to the schedule described in the protocol.

Safety assessment methods:

Safety was evaluated from reported AEs, scheduled physical examinations, vital sign measurements, 12-lead electrocardiogram (ECG) findings, and clinical laboratory test results. Pharmacokinetic analytical methods:

In part 1 , blood samples (10 ml. each) were obtained on study days 16 and 27 immediately before dose administrations for trough analysis of orally administered bifeprunox. A blood sample was collected at the time of discontinuation if a subject withdrew from the study early. Individual and summary plasma concentration data for bifeprunox were reported. Statistical Methods: The primary endpoints were the proportion of subjects spontaneously reporting AEs of nausea and vomiting over the titration days (up to 20 mg) plus 2 additional dose administration days at 20 mg. The primary analysis was the comparison of the proportions of subjects among treatment groups by the Fisher exact test (parts 1 to 3). Estimates of proportions and corresponding 2-sided exact 90% CIs (equivalent to a 1 -sided 95% Cl) for each treatment group were provided. For study progression from part 1 to 2, treatment was deemed unacceptable if a lower bound of the 2-sided exact 90% Cl (equivalent to a 1 -sided 95% Cl) for nausea and vomiting rates was greater than 1 1% and 9%, respectively. An acceptable profile was based on the overall tolerability results.

Descriptive statistics were provided for bifeprunox trough concentrations. Using predetermined criteria, individual data for vital signs measurements, 12-lead ECG findings, and laboratory test results were evaluated for potential clinical importance (PCI). Descriptive statistics including N, mean, minimum, maximum, standard deviation (SD), and standard error (SE), were computed for safety data for each treatment group and each time point. SUMMARY-CONCLUSIONS

Safety Results: At least 1 TEAE was reported by 21 (87.5%) subjects in the 14-day cohort, 22 (84.6%) subjects in the 25-day cohort, and 5 (83.3%) subjects in the placebo cohort.

The most frequently reported TEAEs in either the 14-day or 25-day cohort were nausea, headache, postural orthostatic tachycardia syndrome, and dizziness. Nausea was reported for 1 1 (45.8%), 3 (1 1.5%), and 0 subjects in the 14-day, 25-day, and placebo cohorts, respectively. Headache was reported for 8 (33.3%), 1 1 (42.3%), and 4 (66.7%) subjects in the 14-day, 25-day, and placebo cohorts, respectively. Postural orthostatic tachycardia syndrome was reported for 5 (20.8%), 9 (34.6%), and 3 (50.0%) subjects in the 14-day, 25-day, and placebo groups, respectively. Dizziness was reported for 5 (20.8%), 6 (23.1 %), and 1 (16.7%) subjects in the 14-day, 25-day, and placebo cohorts, respectively. The primary objective of the study was to evaluate different titration regimens to a total daily dose of 20 mg of bifeprunox, to determine which would allow an acceptable level of AEs. The primary endpoints of the study were the proportions of subjects spontaneously reporting TEAEs of nausea or vomiting over the titration days (up to 20 mg) plus 2 additional dose administration days at 20 mg. The treatment was deemed acceptable if the lower bound of the 2-sided 90% Cl for nausea and vomiting rates was less than or equal to 11 % and 9%, respectively. For this analysis, data were excluded from the 4 subjects who withdrew from the study and thus did not have data for the full titration and 3 days of dose administration with 20 mg. None of these subjects had nausea or vomiting.

Nausea was reported by 11 (47.8%) and 3 (12.5%) subjects in the 14-day (lower bound CI=30) and 25-day cohorts (lower bound Cl=3), respectively. All incidences of nausea were considered to be drug related. In the 14-day cohort, of the 1 1 incidences of nausea, 5 were mild in intensity and 6 were moderate in intensity. All 3 incidences of nausea, which occurred in the 25-day cohort, were mild in intensity.

Vomiting was reported by 4 (17.4%) subjects in the 14-day cohort (lower bound Cl=6). All 4 incidences of vomiting were considered to be drug related. Of the 4 incidences, 3 were mild and 1 was moderate in intensity. No serious adverse events (SAEs) or deaths were reported during the study period. PCI changes in laboratory test results were reported for 19 subjects (34.0%) and vital sign measurements for 43 subjects (77.0%).

Pharmacokinetic Results: Mean trough bifeprunox levels on days 16 and 27 (after a 14-day and 25-day titration, respectively) were 6.8 and 4.0 ng/mL, respectively. These values are in agreement with those seen in previous bifeprunox studies. Conclusions: The purpose of this study was to evaluate different regimens of titration to a total daily bifeprunox dose of 20 mg, while achieving an acceptable incidence of AEs in healthy subjects.

The safety results were as follows: Based on the rules for study progression, the study was stopped in part 1 because the lower bound of the 2-sided 90% Cl for nausea was greater than 1 1 % in the 14-day titration cohort (incidence [Cl]=47.8% [30%, 66%]).

The 25-day titration regimen met the acceptable level of incidence of nausea (incidence [CI]=I 2.5% [3%, 29%]) and vomiting, whereas the 14-day regimen did not meet an acceptable level of incidence for nausea. At least 1 TEAE was reported by 21 (87.5%) subjects in the 14-day cohort, 22 (84.6%) subjects in the 25-day cohort and 5 (83.3%) subjects in the placebo cohort. The most frequently reported TEAEs in either the 14-day or 25-day cohort were nausea, headache, postural orthostatic tachycardia syndrome, and dizziness. All symptoms were mild or moderate in intensity. There were 4 discontinuations from the study. None were related to intolerance.

No SAEs or deaths occurred during the course of this study; however, 1 pregnancy was reported within the time period for SAE.

Claims

1. Use of at least one bifeprunox compound for the manufacture of a composition regimen of incrementally increasing dosages of the at least one bifeprunox compound to be used for titration over a period of time up to a maintenance dosage for the treatment of at least one central nervous system condition, comprising a plurality of unit dosages of the at least one bifeprunox compound, wherein the titration takes place over 20 to 28 days and the dosage of the at least one bifeprunox compound over the entire titration schedule increases incrementally to reach a maintenance dosage of 20 mg/day.

2. Use according to claim 1 , wherein each unit dosage of the at least one bifeprunox compound in the composition regimen comprises a different dosage strength of the at least one bifeprunox compound.

3. Use according to claim 1 , wherein in the composition regimen sets of two, three or four unit dosages of the at least one bifeprunox compound comprise the same dosage strength of the at least one bifeprunox compound in each set.

4. Use according to claim 3, wherein in the composition regimen sets of three unit dosages of the at least one bifeprunox compound comprise the same dosage strength of the at least one bifeprunox compound.

5. Use according to any one of claims 1-4, wherein in the titration takes place over 21 days.

6. Use according to any one of claims 1-5, wherein the starting dosage ranges from about 0.05 mg to about 0.15 mg.

7. Use according to any one of claims 3 to 6, wherein the unit dosages are chosen from single strength dosages ranging from about 0.05 mg to about 0.07 mg, from about 0.07 mg to about 0.18 mg, from about 0.18 mg to about 0.35 mg, from about 0.35 mg to about 0.70 mg, from about 0.70 mg to about 1.4 mg, from about 1.4 to about 3.5 mg, from about 3.5 to about 7.0 mg, from about 7.0 to about 14.0 mg, and from about 14.0 to about 20.0 mg.

8. Use according to claim 7 wherein the unit dosages are chosen from single strength dosages from about 0.0550 mg to about 0.0675 mg, from about 0.10 mg to about 0.15 mg, from about 0.20 mg to about 0.30 mg, from about 0.4 mg to about 0.6 mg, from about 0.8 mg to about 1.2 mg, from about 1.5 mg to about 2.5 mg, from about 4.0 to about 6.0 mg, from about 8.0 mg to about 12.0 mg, and from about 15.0 mg to about 20.0 mg.

9. Use according to claim 8, wherein the unit dosages are chosen from single strengths dosages 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.

10. Use according to any one of claims 3-9, wherein in the composition regimen the increase in strength of the at least one bifeprunox compound in a dosage unit is about 1.5 to 3 times the strength of the at least one bifeprunox compound in the unit dosages of the preceding set of dosage units.

1 1. Use according to any one of claims 1-10 wherein the at least one bifeprunox compound is bifeprunox mesylate.

12. Use according to claim 11 , wherein bifeprunox mesylate is in the alpha polymorphic form.

13. Use according to any one of claims 1-12, wherein the composition regimen is used for cross-titration.

14. Use according to any one of claims 1 -13, wherein the titration takes place over 21 days, wherein the composition regimen comprises seven sets of three unit dosages of the at least one bifeprunox compound, each set comprising unit dosages of the same dosage strength of the at least one bifeprunox compound, starting at a dosage strength of 0.125 mg followed by consecutive strengths of 0.25 mg, 0.5 mg, 1.0 mg, 2.0 mg, 5.0 mg and 10 mg and wherein at day 22 the maintenance dosage is reached.

15. Use according to any one of claims 1-13, wherein the titration takes place over 28 days, wherein in the composition regimen comprises seven sets of four unit dosages of the at least one bifeprunox compound, each set comprising unit dosages of the same dosage strength of the at least one bifeprunox compound, starting at a dosage strength of 0.125 mg followed by consecutive strengths of 0.25 mg, 0.5 mg, 1.0 mg, 2.0 mg, 5.0 mg and 10 mg and wherein at day 29 the maintenance dosage is reached.

16. A titration kit, comprising 20 to 28 unit dosages, each of the unit dosages comprising at least one bifeprunox compound, wherein the dosage of the at least one bifeprunox compound increases in strength over the entire titration regimen.