EP2059244A1 - Titrationsplan für bifeprunox zur behandlung von schizophrenie und kits zur verwendung damit - Google Patents

Titrationsplan für bifeprunox zur behandlung von schizophrenie und kits zur verwendung damit

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Publication number
EP2059244A1
EP2059244A1 EP07802974A EP07802974A EP2059244A1 EP 2059244 A1 EP2059244 A1 EP 2059244A1 EP 07802974 A EP07802974 A EP 07802974A EP 07802974 A EP07802974 A EP 07802974A EP 2059244 A1 EP2059244 A1 EP 2059244A1
Authority
EP
European Patent Office
Prior art keywords
bifeprunox
strength
titration
compound
unit dosages
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07802974A
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English (en)
French (fr)
Inventor
Antje A. Winsemius
Pieter W.A.J. Van Den Broeck
Luigi M. Barbato
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Healthcare Products BV
Original Assignee
Solvay Pharmaceuticals BV
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Filing date
Publication date
Application filed by Solvay Pharmaceuticals BV filed Critical Solvay Pharmaceuticals BV
Priority to EP07802974A priority Critical patent/EP2059244A1/de
Publication of EP2059244A1 publication Critical patent/EP2059244A1/de
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • 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).
  • CNS central nervous system
  • hydrochloric acid salt of the above-referenced formula i.e., (7-[4- ([1 ,1'-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone, 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.
  • 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.
  • Bifeprunox (earlier known as DU 127090) binds to dopamine D 2 -like receptors and 5-HT 1A receptors; it is a partial agonist at dopamine D 2 / 3 receptors and also a partial agonist at serotonin 5-HT 1A receptors.
  • Bifeprunox's affinity for both the dopamine D 2 and serotonin 5-HT 1A receptors makes it useful for the treatment of schizophrenia and other psychotic disorders.
  • bifeprunox can be of value for the treatment of affections or diseases of the CNS caused by disturbances in either the dopamine or serotinergic 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.
  • the length of the titration period and the dosages used and the increments thereof are, however, drug-dependent. Therefore, there is a need to find a suitable titration schedule for safe and effective inititiation of the treatment with bifeprunox. It has now been surprisingly discovered that the tolerability to the compound can be improved and the occurrence of at least one of the undesired side effects can be reduced or prevented by gradual increase of the bifeprunox compound dose according to the titration schedule of this invention.
  • 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 the compound 7-[4-([1 , 1 '-biphenyl]-3-ylmethyl)-1 -piperazinyl]-2(3H)-benzoxazolone monomethane-sulfonate (INN bifeprunox).
  • the present invention is related to a composition regimen for use in a titration schedule for titrating dosages of the at least one bifeprunox compound 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 a composition, each of the unit dosages comprising at least one bifeprunox compound, wherein period of time of the titration schedule comprises at least six time segments and the dosage of the at least one bifeprunox compound over the entire titration schedule increases in strength each time segment.
  • a titration kit comprising at least six sequential unit dosages, each of the unit dosages comprising at least one bifeprunox compound, and wherein the unit dosages are of increasing strengths over the entire titration period.
  • the present invention is related to a method for a titration schedule for initiating the treatment at least one central nervous system condition in a subject in need thereof comprising administering to the subject a composition regimen comprising a plurality of unit dosages of the composition, each of the unit dosages comprises at least one bifeprunox compound, wherein the unit dosages over the entire titration schedule increase in amount of the at least one bifeprunox compound.
  • a method for reducing at least one side effect associated with the initiation of a bifeprunox treatment comprising administering a composition regimen comprising a plurality of unit dosages of a composition, each of the unit dosages comprises at least one bifeprunox compound according, wherein the unit dosages over the titration schedule increase in an amount of the at least one bifeprunox compound.
  • Bifeprunox compounds are indicated for the treatment of CNS disorders including schizophrenia, other psychotic disorders and Parkinson's disease.
  • dosage strength are expressed in an amount equivalent to bifeprunox base.
  • bifeprunox base refers to the compound 7-[4-([1 ,1'-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxa-zolone (INN
  • the typical dosing regimen ranges from amounts equivalent to 0.05 mg to 60 mg bifeprunox base; doses may vary based in part on the severity of the CNS condition and other conditions of the patient.
  • a titration schedule dose or a maintenance dose for bifeprunox compounds can be a dose equivalent to 10 mg/day, 20 mg/day, 30 mg/day or 40 mg/day of bifeprunox base.
  • the efficacy, safety and tolerability profile of bifeprunox suggests it may be an effective agent to employ as a treatment option for patients with schizophrenia.
  • bifeprunox treatment can result in adverse events during initiation of treatment, which may lead to the discontinuation of bifeprunox treatment and/or inconsistent use of the treatment.
  • bifeprunox compound(s) refers to the active compound 7-[4-([1 ,1'-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxa-zolone, its N- oxide and pharmaceutically acceptable salts, solvates and hydrates thereof and solvates and hydrates of the salts.
  • N-oxide 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.
  • pharmaceutically acceptable salts of bifeprunox or its N-oxide may be obtained using standard procedures well known in the art, for example, by mixing a compound of the present invention with a suitable acid, for instance an inorganic acid or an organic acid.
  • the at least one bifeprunox compound comprises bifeprunox mesylate.
  • the at least one bifeprunox compound is bifeprunox mesylate.
  • the bifeprunox mesylate may be chosen from the ⁇ , Y, or ⁇ crystalline polymorphic forms, and mixtures thereof.
  • the at least one bifeprunox compound comprises at least one polymorphic form chosen from the ⁇ and Y polymorphic forms.
  • the crystalline polymorphic form of ⁇ bifeprunox mesylate according to the present disclosure (which is the preferred polymorphic form) is defined by at least the physicochemical parameters as disclosed in WO 2005/016898.
  • the term "titration schedule" refers to a regimen of dosages of a pharmaceutically active agent over a period of time, based in part on a target dose and/or a maintenance dose.
  • the target dose and/or maintenance dose can be a dose equivalent to at least 10 mg/day, at least 20 mg/day, at least 30 mg/day or at least 40 mg/day of bifeprunox base and, for example, 10 mg/day, 20 mg/day, 30 mg/day or 40 mg/day of bifeprunox base.
  • a target dose is 20 mg/day of at least one bifeprunox compound.
  • the target dose is 40 mg/day of at least one bifeprunox compound.
  • 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 6 to 14 consecutive days, such as 6 to 10 days and further for example, from 6 to 8 days and in particular seven days.
  • the period of time can be divided into time segments other than one day, such as two or three days segments.
  • the same unit dosage of bifeprunox compound can be administered every day within the time segment, wherein the administration may be once daily the full dosage, but also, for example, twice daily half of the dosage.
  • the period over which the titration schedule spans may be in part due to the lowest dose with which the titration starts, the amount of increase considered clinically acceptable and the target and/or maintenance dose; for example, a titration schedule may span over a larger number of days (such as 14 days) it may span over a shorter period of time (such as 6 or 7 days). Therefore an embodiment of the present invention is a titration schedule wherein the number of time segments is at least six and with a titration period of at least six, twelve or eighteen days, respectively. Another embodiment relates to is a titration schedule wherein the number of time segments is at least seven and with a titration period of at least seven, fourteen or twenty one days, respectively.
  • the strength or amount of bifeprunox compound in each unit dosage increases incrementally over the subsequent titration schedule until a target dose and/or maintenance dose is reached.
  • consecutive strengths or amounts of unit dosages may be given during the course of the titration such that over the entire titration schedule, an overall increase in strength or amount of the unit dosage results. For example, comparing the first unit dose to the last unit dose before the maintenance unit dosage is administered, there is an increase in the amount of bifeprunox compound being administered.
  • 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 28 mg.
  • the strength can be subsequent strengths within the group indicated above.
  • 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 25 mg of a bifeprunox compound.
  • the strength can be subsequent strengths within the group indicated above.
  • 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.
  • the unit dosages may increase in an amount or strength of the bifeprunox compound ranging from about 1.5 to 3 times that of the preceding dose and further for example, from about 2 to 2.5 times that of the preceding dose.
  • a preceding dosage is available for consideration.
  • composition regimen provided in the present disclosure can be in the form of a kit comprising, e.g., a plurality of unit dosages in the form of tablets for the titration schedule to arrive at the final and/or maintenance dose.
  • the present invention is further directed to a kit for a titration schedule to facilitate the treatment of at least one central nervous system condition comprising a plurality of unit dosages of a composition comprising at least one bifeprunox compound, wherein the unit dosages over the titration schedule increase in an amount of the bifeprunox compound.
  • An embodiment therefore relates to a titration kit, comprising at least six sequential unit dosages, each of the unit dosages comprising at least one bifeprunox compound, wherein the unit dosages are of increasing strengths over the entire titration period.
  • the strengths or amounts of each unit dosage can be chosen from the groups of different strengths indicated above.
  • the titration period of the kit is divided in at least six time segments (as defined previously).
  • the kit as described above 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 dose than another tablet and further for example, having indicia disposed adjacent to the tablets for displaying successive strengths and/or successive days.
  • a package such as a blister package
  • the package comprising a plurality of tablets, e.g., each tablet having a different dose than another tablet and further for example, having indicia disposed adjacent to the tablets for displaying successive strengths and/or successive days.
  • 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.
  • dosage forms can be prepared by mixing, individually or together, the polymorphic forms of the bifeprunox compound (e.g., ⁇ , ⁇ and/or ⁇ of bifeprunox mesylate) with inert pharmaceutically acceptable excipients, carriers and/or pharmaceutically acceptable ingredients.
  • the active ingredients i.e., a bifeprunox compound
  • the active ingredients 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.
  • compositions of the present disclosure can comprise at least one pharmaceutical excipient.
  • 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, thal
  • 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.
  • Tablets with a strength of 10 mg were prepared according to the following procedures (required quantities for all strengths are given in the Table below): [031] The microcrystalline cellulose was added to bin blender A and mixed for five (5) minutes to distribute. The material was transferred to bin blender B and mixed for five (5) minutes to distribute. The following ingredients were added to bin blender B; half (V-O portion of lactose monohydrate bifeprunox mesylate, sodium starch glycolate and remaining half (V-O portion of lactose monohydrate and mixed for twenty-five (25) to thirty-five (35) minutes.
  • the granulation was milled/de-agglomerated with a rotating impeller- screening mill using a conical screen equipped with a 0.6 mm screen or 0.8 mm screen.
  • the granulation was transferred to a bin blender A.
  • To bin blender A sodium stearyl fumarate and colloidal silicon dioxide (for 20 mg only) was added and sieved through a #20 mesh.
  • the granulation was mixed for a target of ten (10) to twenty-five (25) minutes, at 6 to 8 rpm.
  • the granulation was compressed on the rotary tablet press and collected in suitable containers.
  • Tablets with a strength 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 were prepared in a corresponding manner by decreasing or increasing the amount of bifeprunox mesylate compensating with the amount of lactose monohydrate and/or microcrystalline cellulose to come to the same final weight, with the understanding that a different coating component was used in order to obtain a different color for every tablet strength (see Table 1 ).
  • EXAMPLE 3 CLINICAL STUDY [035] This study represented a randomized, double-blinded, placebo- controlled, sequential panel, rapid titration study of the safety and tolerability of bifeprunox compounds in subjects with schizophrenia. In particular, this study assessed the safety, tolerability and efficacy after a rapid titration of bifeprunox to a therapeutic dose of 40 mg/day in schizophrenia and schizoaffective subjects. Eligible subjects were hospitalized at the start of the screening period and entered a single- blind placebo run-in period (day -7 to -1 ) to assure that the 7-day antipsychotic drug- free criterion was met prior to bifeprunox titration.
  • Each listed dose in the titration schedule was administered once daily (QD) followed by the next higher dose the following day. If a subject did not tolerate a given dose, the subject was allowed to repeat that same dose for one extra day before increasing the dose to the next level. Only one repeat dose, however, was allowed during the entire titration period. Upon reaching the high proposed dose of 40 mg/day, the subject entered a 3-day maintenance period for this dose. Final assessments were performed on the day after the last maintenance period dose and follow-up assessments were performed 3 days after the last dose of study treatment.
  • Efficacy assessments i.e., Positive and Negative Symptoms of Schizophrenia (PANSS) and Clinical Global Impression-Severity (CGI-S) were performed at screening, Day-1 and at the final assessment; Clinical Global Impressions-Improvement (CGI-I)) was performed at the final assessment only. Safety was monitored throughout the study by assessment of physical examination, vital signs, adverse events (AEs), concomitant medications, clinical laboratory assessments, 12- lead electrocardiograms (ECGs), Simpson-Angus Scale (SAS) score and Barnes
  • AAS Akathisia Scale
  • the treatment phase lasted approximately two weeks, including follow-up assessment. Subjects remained hospitalized until the post- treatment follow-up assessment was completed or until their condition had clinically stabilized.
  • Bifeprunox were tablets taken orally at a total daily dose of 0.25 mg to 40 mg in the following titration schedules:
  • Placebo tablets matching the bifeprunox tablets were taken orally using the same dosing regimen as the test product were administered.
  • titration schedule 2c appeared to reduce the AEs observed during titration schedule 1 , indicating an advantage with a more gradual increase from 0.25 mg to 10 mg and then up to 40 mg doses using a 7-day rather than 6-day titration schedule.
  • All subjects in the bifeprunox group in titration schedule 1 reported at least one treatment of emergent adverse event (TEAE).
  • TEAE emergent adverse event
  • Adverse events were most commonly reported between 0.25 mg to 10 mg dose levels, particularly at the 5 mg dose.
  • the most commonly observed TEAEs were nervous system disorders (somnolence, dizziness, headache NOS and gait abnormal NOS), and gastrointestinal disorders (nausea and vomiting).
  • Orthostatic hypotension was also reported at the 1 , 5, 10, and 40 mg dose levels. No TEAEs occurred at the 20 mg dose level. All subjects receiving bifeprunox in titration schedule 1 were considered to have at least 1 TEAE which was related to study treatment; all TEAEs occurring in the nervous system were considered to be related to study treatment. Three subjects receiving bifeprunox in titration schedule 1 reported TEAEs which were considered to be severe, with the most commonly reported events occuring in the nervous system. Severe TEAEs of orthostatic hypotension, nausea, vomiting NOS, and rigors were reported. All severe TEAEs occurred at the 1 , 5 and 10 dose levels.
  • titration schedule 1 In contrast to titration schedule 1 , fewer subjects reported events of somnolence which were considered to be related to the study treatment, which no TEAEs of anorexia, gait abnormal NOS or orthostatic hypotension were reported. Three subjects receiving bifeprunox in titration schedule 2c reported TEAEs which were considered to be severe. All three subjects reported severe TEAEs of dizziness and a severe TEAE of pallor was reported in one subject. All severe TEAEs occurred at the 2 mg and 5 mg dose level. One subject, receiving placebo in titration schedule 2c, reported an serious adverse event (SAE) (face injury).
  • SAE serious adverse event
  • titration schedule 1 Subjects in titration schedule 1 received bifeprunox at doses of 0.25, 1 , 5,10,20, and 40 mg over 6 consecutive days. In this titration schedule, most AEs occurred in the 0.25 to 10 mg dose range. Once the 10 mg dose was reached, daily increases to 20 to 40 mg were well-tolerated. Titration schedule 2c had a slower titration up to the 10 mg level with subjects dosed at 0.25, 0.5, 2, 5, 10, 20, and 40 mg bifeprunox over 7 consecutive days. This longer and more conservative titration schedule resulted in fewer withdrawals from the study due to intolerable effects and appeared to reduce the AEs observed during titration schedule 1.
  • Bifeprunox exposure was approximately 1.3 to 1.5 times higher in titration schedule 2c than titration schedule 1 on the final study day, while exposure was comparable between the 2 schedules for the metabolites.
  • the results of this study generally indicated that titration of bifeprunox from 0.25 mg to 40 mg over 7 days was better tolerated than titration over a 6-day period. It, however, should be noted that the final, maintenance dose of this study was 40 mg and the titration schedule, i.e., 6 to 7 days, was based in part on the level of this final, maintenance dose.

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  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Addiction (AREA)
  • Anesthesiology (AREA)
  • Inorganic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP07802974A 2006-08-31 2007-08-29 Titrationsplan für bifeprunox zur behandlung von schizophrenie und kits zur verwendung damit Withdrawn EP2059244A1 (de)

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US84124406P 2006-08-31 2006-08-31
EP06119936 2006-08-31
US84149506P 2006-09-01 2006-09-01
EP06120016 2006-09-01
EP07802974A EP2059244A1 (de) 2006-08-31 2007-08-29 Titrationsplan für bifeprunox zur behandlung von schizophrenie und kits zur verwendung damit
PCT/EP2007/058957 WO2008025780A1 (en) 2006-08-31 2007-08-29 Titration schedule for bifeprunox for treating schizophrenia and kits for use therein

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EP2059244A1 true EP2059244A1 (de) 2009-05-20

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EP07802974A Withdrawn EP2059244A1 (de) 2006-08-31 2007-08-29 Titrationsplan für bifeprunox zur behandlung von schizophrenie und kits zur verwendung damit

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JP (2) JP2010501625A (de)
KR (1) KR20090063228A (de)
AU (2) AU2007291234A1 (de)
BR (1) BRPI0715445A2 (de)
CA (2) CA2661120A1 (de)
EA (1) EA200970239A1 (de)
IL (1) IL196867A0 (de)
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WO2010060742A1 (en) * 2008-11-03 2010-06-03 Solvay Pharmaceuticals B.V. Combination of bifeprunox and an antipsychotic drug with d2/5-ht2a receptor antagonistic activity for treating cns disorders
WO2010070061A1 (en) * 2008-12-19 2010-06-24 Abbott Healthcare Products B.V. Compositions, kits and methods of a titration schedule for bifeprunox compounds
AU2010266018B2 (en) 2009-06-25 2014-01-09 Alkermes Pharma Ireland Limited Heterocyclic compounds for the treatment of neurological and psychological disorders
WO2011023796A1 (en) 2009-08-31 2011-03-03 Abbott Healthcare Products B.V. Bifeprunox for treating addiction
CA2885196C (en) 2012-09-19 2021-06-22 Alkermes Pharma Ireland Limited Pharmaceutical compositions having improved storage stability
WO2015143145A1 (en) 2014-03-20 2015-09-24 Alkermes Pharma Ireland Limited Aripiprazole formulations having increased injection speeds
US11273158B2 (en) 2018-03-05 2022-03-15 Alkermes Pharma Ireland Limited Aripiprazole dosing strategy

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CA2250347C (en) 1996-03-29 2006-02-21 Duphar International Research B.V. Piperazine and piperidine compounds with high affinity for dopamine-d2 and serotonin-5ht1a receptors
CA2310950C (en) * 2000-04-03 2005-11-08 Janssen Pharmaceutica N.V. An efficacious dosage regiment of galantamine that reduces side effects
AR034206A1 (es) 2001-02-16 2004-02-04 Solvay Pharm Bv Un procedimiento para la preparacion de mesilatos de derivados de piperazina y dichos mesilatos
AR045362A1 (es) * 2003-08-18 2005-10-26 Solvay Pharm Bv Forma cristalina estable de mesilato de bifeprunox (monometansulfonato de 7-[4-([1,1- bifenil] -3- ilmetil) -1- piperazinil] - 2-(3h) -benzoxazolona
US7423040B2 (en) * 2005-02-18 2008-09-09 Irene Eijgendaal Stable crystalline form of bifeprunox mesylate, dosage forms thereof and methods for using same
RU2394821C2 (ru) 2005-08-22 2010-07-20 Солвей Фармасьютикал Б.В. N-оксиды как пролекарства производных пиперазина и пиперидина

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WO2008025781A1 (en) 2008-03-06
EA200970239A1 (ru) 2009-08-28
CA2661800A1 (en) 2008-03-06
CA2661120A1 (en) 2008-03-06
JP2010501625A (ja) 2010-01-21
NO20091243L (no) 2009-03-25
AU2007291234A1 (en) 2008-03-06
BRPI0715445A2 (pt) 2014-05-13
AU2007291235A1 (en) 2008-03-06
WO2008025780A1 (en) 2008-03-06
IL196867A0 (en) 2009-11-18
EP2059245A1 (de) 2009-05-20
KR20090063228A (ko) 2009-06-17
JP2010501626A (ja) 2010-01-21

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