FIG. 1
`
`ng/ml
`
`1
`
`k
`1
`
`\
`~'
`.
`
`i
`
`t
`\' ‘r
`t
`
`3'
`o
`
`.
`
`~
`
`:
`
`r
`:
`
`x
`
`Plasma Concentration
`
`\
`
`:
`
`:
`t
`
`\
`
`1
`:
`
`1
`
`1
`.
`1
`
`‘
`‘
`:
`
`:
`
`:
`:
`
`‘
`
`:
`:
`
`;-
`
`r.
`.
`:3
`
`'»
`:4
`
`:
`
`:
`:
`
`:
`:
`
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`
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`»
`l
`
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`
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`i
`
`.~
`
`3
`3
`
`~
`x
`«
`
`3
`q
`'\
`xx
`
`0.1
`
`
`18 2
`36
`50
`64
`78
`92
`106120
`
`
`
`Days
`
`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 1, p. 001
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 1, p. 001
`
`

`

`FIG. 2
`
`Plasma Concentration
`
`1 00
`
`:8\\\\\
`7.5§\\\\\\\\\\\§\\
`
`:
`
`-;—-
`
`$
`
`ng/ml
`
`3 .5-
`
`
`
`=
`
`.
`
`{
`
`.~
`
`-
`¥
`Q
`
`.
`:
`
`I
`
`-,
`
`Q
`
`\
`
`.
`
`4
`
`0_3 __
`
`..
`
`__
`
`__
`
`__
`
`__
`
`__
`
`_
`
`0.1
`
`18 22 36
`
`50
`
`64
`
`78 92106120
`
`Days
`
`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 1, p. 002
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 1, p. 002
`
`

`

`FIG. 3
`
`Plasma Concentration
`
`250
`
`ng/ml
`
`7-5
`
`A
`I I I
`4O \\\\\\\\\\\\\\\\‘ I:‘I
`\xxxx \\\X \\\\\\‘\\\\\\\.
`20 \\\\\\\\\\\\\\\\\\\\\\\C
`
`W \\\\\\5\
`
`
`
`__
`
`__
`
`__
`
`_.
`
`_.
`
`__
`
`__
`
`__
`
`__
`
`__
`
`__
`
`a.
`
`0_3
`
`0.1
`
`18 22 36
`
`50
`
`64 78 92 106120
`
`Days
`
`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 1, p. 003
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 1, p. 003
`
`

`

`Please type a plus sign (+) inside this box
`
`
`
`+
`
`
`
`
`PTO/SB/Ot (1000)
`Approved for use through 10/31/2002. OMB 0651-0032
`U.S. Patent and Trademark Office; US. DEPARTMENT OF COMMERCE
`Underthe Pa erwork Reduction Ac of 1995, no ersons are re uired to resond to a collection of information unless it contains a valid OMB control number.
`
`DECLARATION
`AND
`
`Attorne Docket Number
`
`PRD2901USNP
`
`POWER OF ATTORNEY
`FOR UTILITY 0R DESIGN
`PATENT APPLICATION
`
`(37 CFR 1.63)
`
`[I Declaration Submitted with X Declaration Submitted after
`Initial Filing
`0R
`Initial Filing
`(Surcharge
`(37 CFR1.16(e)) required)
`
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`COMPLETE IF KNOWN
`
`Application Number
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`As a below named inventor, I hereby declare that:
`
`My residence, mailing address, and citizenship are as stated below next to my name.
`I believe I am the original, first and sole inventor (if only one name is listed below) or an original, first and joint inventor (if
`plural names are listed below) of the subject matter which is claimed and for which a patent is sought on the invention
`entitled:
`
`
`
`DOSING REGIMEN ASSOCIATED WITH LONG ACTING INJECTABLE
`
`the specification of which
`
`IE is attached hereto
`
`OR
`
`I:I was filed on (MM/DD/YYYY) as United States Application Number or PCT International Application Number
`and was amended on (MM/DD/YYYY) |:|
`
`I hereby state that l have reviewed and understand the contents of the above identified specification, including the claims, as
`amended by any amendment specifically referred to above.
`
`I acknowledge the duty to disclose information which is material to patentability as defined in 37 CFR 1.56, including for
`continuation-in-part applications, material information which became available between the filing date of the prior application
`and the national or PCT international filing date of the continuation-in-part application.
`
`Certified Copy
`Attached?
`YES
`
`NO
`
`
`
`I hereby claim foreign priority benefits under 35 U.S.C. 119( )-(d) or 365(b) of any foreign application(s) for patent or
`inventor's certificate, or 365(a) of any PCT international application which designated at least one country other than the
`United States of America, listed below and have also identified below, by checking the box, any foreign application for patent
`or inventor's certificate, or any PCT international application having a filing date before that of the application on which
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`III
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`I:I Additional foreion ao olication numbers are listed on a sm olemental oriorit data sheet PTO/SB/OZB attached hereto:
`
`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 1, p. 004
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 1, p. 004
`
`

`

`DECLARATION - Utility or Design Patent Application
`
`| hereb claim the benefit under 35 U.S.C. 119 e of an United States orovisional aoolication s listed below.
`Ao olication Number 5
`Filino Date MMIDDIYYYY
`
`61/014 918
`I
`61/120,276
`
`12/19/2007
`12/05/2008
`
`Additional provisional application
`numbers are listed on a
`
`supplemental priority data sheet
`PTO/SB/OZB
`h d h
`.
`attac e
`ereto
`
`I hereby claim the benefit under Title 35, United States Code, §120 of any United States application(s) listed below and, insofar
`as the subject matter of each of the claims of this application is not disclosed in the prior United States application in the manner
`provided by the first paragraph of Title 35, United States Code, §112, I acknowledge the duty to disclose material information as
`defined in Title 37, Code of Federal Regulations, s1.56(a) which occurred between the filing date of the prior application and the
`national or PCT international filino date of this ao olication:
`
`Application Serial No.
`
`Filing Date
`
`
`
`I hereby appoint:
`
`Practitioners atCustomer Number
`
`000027777
`
`a
`
`AND
`
`I:I
`
`Practitioner(s) named below:
`Name
`
`Registration Number
`
`Place Customer
`Number Bar Code
`Label Here
`
`as my/our attorney(s) or agent(s) to prosecute the application identified above, and to transact all business in the United
`States Patent and Trademark Office connected therewith.
`
`Address all telephone calls to Hal B. Woodrow at telephone number (732) 524-2976.
`
`Direct all correspondence to:
`
`E or Bar Code Label
`
`000027777
`
`El Correspondence address below
`
`Customer Number
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`Telephone:
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`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 1, p. 005
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 1, p. 005
`
`

`

`I hereby declare that all statements made herein of my own knowledge are true and that all statements made on
`information and belief are believed to be true; and further that these statements were made with the knowledge
`that willful false statements and the like so made are punishable by fine or imprisonment, or both, under 18
`U.S.C. 1001 and that such willful false statements mayjeopardize the validity of the application or any patent
`issued thereon.
`
`NAME OF SOLE OR FIRST INVENTOR:
`
`[I A petition has been filed for this unsined inventor
`
`Given Name
`first and middle if an
`
`An
`
`Family Name
`or Surname
`
`Vermeulen
`
`Inventor’s
`Si . nature
`
`Date
`
`Residence: Ci Beerse
`
`State BE
`
`Count
`
`BE
`
`CitizenshipBE
`
`
`Mailing Address Turnhoutseweg 30
`
`Country BE
`Beerse
`City
`I hereby declare that all statements made herein of my own knowledge are true and that all statements made on
`information and belief are believed to be true; and further that these statements were made with the knowledge
`that willful false statements and the like so made are punishable by fine or imprisonment, or both, under 18
`U.S.C. 1001 and that such willful false statements mayjeopardize the validity of the application or any patent
`issued thereon.
`
`NAME OF SECOND INVENTOR:
`
`El A petition has been filed for this unsined inventor
`
`Given Name
`first and middle if an
`
`Alfons
`
`Family Name
`or Surname
`
`Wouters
`
`—_Si - nature
`
`
`
`____
`I hereby declare that all statements made herein of my own knowledge are true and that all statements made on
`information and belief are believed to be true; and further that these statements were made with the knowledge
`that willful false statements and the like so made are punishable by fine or imprisonment, or both, under 18
`U.S.C. 1001 and that such willful false statements mayjeopardize the validity of the application or any patent
`issued thereon.
`
`NAME OF THIRD INVENTOR:
`
`El A petition has been filed for this unsiuned inventor
`
`Given Name
`first and middle if an
`
`Inventor’s
`Si . nature
`
`Family Name
`or Surname
`
`Mailino Address
`____
`
`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 1, p. 006
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 1, p. 006
`
`

`

`I hereby declare that all statements made herein of my own knowledge are true and that all statements made on
`information and belief are believed to be true; and further that these statements were made with the knowledge
`that willful false statements and the like so made are punishable by fine or imprisonment, or both, under 18
`U.S.C. 1001 and that such willful false statements mayjeopardize the validity of the application or any patent
`issued thereon.
`
`NAME OF SOLE OR FOURTH
`INVENTOR:
`
`[I A petition has been filed for this unsigned inventor
`
`Given Name
`first and middle if an
`
`Inventor’s
`Signature
`
`Mailino Address
`
`Family Name
`or Surname
`
`
`
`Mailin Address
`____
`I hereby declare that all statements made herein of my own knowledge are true and that all statements made on
`information and belief are believed to be true; and further that these statements were made with the knowledge
`that willful false statements and the like so made are punishable by fine or imprisonment, or both, under 18
`U.S.C. 1001 and that such willful false statements mayjeopardize the validity of the application or any patent
`issued thereon.
`
`I hereby declare that all statements made herein of my own knowledge are true and that all statements made on
`information and belief are believed to be true; and further that these statements were made with the knowledge
`that willful false statements and the like so made are punishable by fine or imprisonment, or both, under 18
`U.S.C. 1001 and that such willful false statements mayjeopardize the validity of the application or any patent
`issued thereon.
`
`NAME OF FIFTH INVENTOR:
`
`I:I A petition has been filed for this unsioned inventor
`
`Given Name
`first and middle if an
`
`Family Name
`or Surname
`
`Inventor’s
`
`Signature
`
`Residence: Ci
`
`Citizenship
`
`NAME OF INVENTOR:
`
`[I A petition has been filed for this unsioned inventor
`
`Family Name
`Given Name
`
`(first and middle [if anyl)
`or Surname
`
`Inventor’s
`Si nature
`
`Mailino Address
`____
`
`Mylan V. Janssen (IPR2020-00440) EX. 1019 Part 1, p. 007
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 1, p. 007
`
`

`

`DOSING REGIMEN ASSOCIATED WITH LONG ACTING INJECTABLE
`
`PALIPERIDONE ESTERS
`
`PRD2901USNP
`
`FIELD OF THE INVENTION
`
`This invention relates to a method of treating patients in need of treatment with
`
`long acting injectable paliperidone palmitate formulations.
`
`BACKGROUND OF THE INVENTION
`
`Antipsychotic medications are the mainstay in the treatment of schizophrenia,
`
`schizoaffective disorder, and schizophreniform disorders. Conventional antipsychotics
`
`were introduced in the mid-1950s. These typical or first generation drugs are usually
`
`effective in controlling the positive symptoms of schizophrenia, but are less effective in
`
`moderating the negative symptoms or the cognitive impairment associated with the
`
`disease. Atypical antipsychotics or second generation drugs, typified by risperidone and
`
`olanzapine, were developed in the 1990s,
`
`and are generally characterized by
`
`effectiveness against both the positive and negative symptoms associated with
`
`schizophrenia.
`
`Paliperidone
`
`palmitate
`
`is
`
`the
`
`palmitate
`
`ester
`
`of
`
`paliperidone
`
`(9-hydroxy-risperidone), a monoaminergic antagonist that exhibits the characteristic
`
`dopamine D2 and serotonin (5-hydroxytryptamine type 2A) antagonism of the
`
`second—generation, atypical antipsychotic drugs. Paliperidone is the major active
`
`metabolite of risperidone. Extcndcd rclcasc (ER) osmotic controlled release oral
`
`delivery (OROS) paliperidone, as a tablet formulation, is marketed in the United States
`
`(U.S.) for the treatment of schizophrenia and maintenance of effect.
`
`Paliperidone palmitate is being developed as a long-acting, intramuscular (i.m.),
`
`injectable aqueous nanosuspension for the treatment of schizophrenia and other
`
`diseases that are normally treated with antipsychotic mediations. Because of extreme
`
`low water solubility, paliperidone esters such as paliperidone palmitate dissolve slowly
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Mylan V. Janssen (IPR2020-00440) Ex. 1019 Part 1, p. 008
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 1, p. 008
`
`

`

`PRD2901USNP
`
`after an i.m. injection before being hydrolyzed to paliperidone and made available in
`
`the systemic circulation.
`
`Many patients with these mental
`
`illnesses achieve symptom stability with
`
`available oral antipsychotic medications; however, it is estimated that up to 75% have
`
`difficulty adhering to a daily oral
`
`treatment regimen,
`
`i.e. compliance problems.
`
`Problems with adherence often result in worsening of symptoms, suboptimal treatment
`
`response, frequent relapses and re—hospitalizations, and an inability to benefit from
`
`rehabilitative and psychosocial therapies.
`
`Paliperidone palmitate injection has been developed to provide sustained plasma
`
`10
`
`15
`
`concentrations of paliperidone when administered once monthly, which may greatly
`
`enhance compliance with dosing. Paliperidone palmitate was formulated as an aqueous
`
`nano suspension as is described in US Patents 6,577,545 and 6,555,544. However,
`
`after the data was analyzed from the clinical trials of this formulation it was discovered
`
`that the absorption of paliperidone from these injections was far more complex than
`
`was originally anticipated. Additionally, attaining a potential therapeutic plasma level
`
`of paliperidone in patients was discovered to be dependent on the site of injection until
`
`steady state concentration is reached. Due to the challenging nature of ensuring an
`
`optimum plasma concentration-time profile for treating patients with paliperidone it is
`
`desirable to develop a dosing regimen that fulfills this goal in patients in need of
`
`20
`
`treatment.
`
`SUMMARY OF THE INVENTION
`
`25
`
`30
`
`In one embodiment of the present invention there is provided a dosing regimen
`
`for administering paliperidone esters to a psychiatric patient in need of treatment
`
`comprising administering intramuscularly in the deltoid a first loading dose from about
`
`100 mg—eq. to about 150 mg—eq. of paliperidone as a paliperidone palmitate formulated
`
`in a sustained release formulation on the first day of treatment; administering
`
`intramuscularly a second loading dose from about 100 mg to about 150 mg-eq of
`
`paliperidone as a paliperidone palmitate formulated in a sustained release formulation
`
`between about the 6th to 10th day of treatment; and administering intramuscularly in
`
`Mylan v. Janssen (IPR2020-00440) EX. 1019 Part 1, p. 009
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 1, p. 009
`
`

`

`PRD2901USNP
`
`the gluteal a maintenance dose of about 25 to about 150 mg-eq. of paliperidone as a
`
`paliperidone ester in a sustained release formulation on between about the 34‘h and
`
`about the 38th day of treatment.
`
`In one embodiment of the present invention there is provided a dosing regimen
`
`for administering paliperidone esters to a psychiatric patient in need of treatment
`
`comprising administering intramuscularly in the deltoid a first loading dose from about
`
`100 mg-eq. to about 150 mg-eq. of paliperidone as a paliperidone palmitate formulated
`
`in a sustained release formulation on the first day of treatment; administering
`
`intramuscularly a second loading dose from about 100 mg to about 150 mg—eq of
`
`paliperidone as a paliperidone palmitate formulated in a sustained release formulation
`
`between about the 6th to 10th day of treatment; and administering intramuscularly in
`
`the gluteal a maintenance dose of about 25 to about 150 mg-eq. of paliperidone as a
`
`paliperidone ester in a sustained release formulation approximately monthly from the
`
`date of the second loading dose.
`
`In another embodiment of the present invention there is provided a dosing
`
`regimen for administering paliperidone palmitate to a psychiatric patient in need of
`
`treatment comprising administering intramuscularly in the deltoid of a patient in need
`
`of treatment a first loading dose from about 100 mg-eq. to about 150 mg-eq of
`
`paliperidone as paliperidone palmitate formulated in a sustained release formulation on
`
`the first day of treatment; administering intramuscularly in the deltoid muscle of the
`
`patient in need of treatment a second loading dose from about 100 mg-eq. to about 150
`
`mg-eq. of paliperidone as paliperidone palmitate formulated in a sustained release
`
`formulation on the eighth day of treatment; and administering intramuscularly in the
`
`deltoid or gluteal muscle of the patient in need of treatment a maintenance dose of
`
`about 25 mg—eq. to about 75 mg—eq. of paliperidone as paliperidone palmitate in a
`
`sustained release formulation on between about the 34th day and the 38th day of
`
`treatment.
`
`In another embodiment of the present invention there is provided a closing
`
`regimen for administering paliperidone palmitate to a psychiatric patient in need of
`
`treatment comprising administering intramuscularly in the deltoid of a patient in need
`
`of treatment a first loading dose of about 150 mg—eq of paliperidone as paliperidone
`
`palmitate formulated in a sustained release formulation on the first day of treatment;
`
`administering intramuscularly in the deltoid muscle of the patient in need of treatment a
`
`3
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Mylan v. Janssen (IPR2020-00440) EX. 1019 Part 1, p. 010
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 1, p. 010
`
`

`

`PRD2901USNP
`
`second loading dose from about 100 mg-eq. of paliperidone as paliperidone palmitate
`
`formulated in a sustained release formulation on the eighth day of treatment; and
`
`administering intramuscularly in the deltoid or gluteal muscle of the patient in need of
`
`treatment a maintenance dose of about 25 mg—eq. to about 75 mg—eq. of paliperidone as
`
`palipcridonc palmitatc in a sustaincd rclcasc formulation approximatcly monthly from
`
`the date of the second loading dose.
`
`In another embodiment of the present invention there is provided a dosing
`
`regimen for administering paliperidone palmitate to a psychiatric patient in need of
`
`treatment comprising administering intramuscularly in the deltoid of a patient in need
`
`of treatment a first loading dose of about 150 mg—eq of paliperidone as paliperidone
`
`palmitatc formulated in a sustained release formulation on the first day of treatment;
`
`administering intramuscularly in the deltoid muscle of the patient in need of treatment a
`
`second loading dose from about 100 mg-eq. of paliperidone as paliperidone palmitatc
`
`formulated in a sustained release formulation on the eighth day of treatment; and
`
`administering intramuscularly in the deltoid or gluteal muscle of the patient in need of
`
`treatment a maintenance dose of about 75 mg-cq. of palipcridonc as palipcridonc
`
`palmitate in a sustained release formulation approximately monthly from the date of the
`
`second loading dose.
`
`In yet another embodiment of the present invention there is provided a dosing
`
`regimen for administering paliperidone esters to a renally impaired psychiatric patient
`
`in nccd of trcatmcnt comprising administcring intramuscularly in thc dcltoid a first
`
`loading dose of about 75mg-eq of paliperidone as a paliperidone palmitatc formulated
`
`in a sustained release formulation on the first day of treatment; administering
`
`intramuscularly a second loading dose of about 75 mg-eq of paliperidone as a
`
`paliperidone palmitate formulated in a sustained release formulation between about the
`
`6th to 10th day of treatment; and administering intramuscularly in the gluteal a
`
`maintenance dose of about 25 mg-eq. to about 75 mg-eq of paliperidone as a
`
`paliperidone palmitatc in a sustained release formulation on between about the 34th and
`
`about the 38th day of treatment.
`
`In yet another embodiment of the present invention there is provided a dosing
`
`regimen for administering paliperidone esters to a renally impaired psychiatric patient
`
`in nccd of trcatmcnt comprising administcring intramuscularly in thc dcltoid a first
`
`loading dose of about lOOmg-eq of paliperidone as a paliperidone palmitate formulated
`
`4
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Mylan v. Janssen (IPR2020-00440) EX. 1019 Part 1, p. 011
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1019 Part 1, p. 011
`
`

`

`PRD2901USNP
`
`in a sustained release formulation on the first day of treatment; administering
`
`intramuscularly a second loading dose of about 75 mg-eq of palipcridone as a
`
`paliperidone palmitate formulated in a sustained release formulation between about the
`
`6th to 10th day of treatment; and administering intramuscularly in the gluteal a
`
`maintenance dose of about 25 mg-cq. to about 75 mg-cq of palipcridone as a
`
`paliperidone palmitate in a sustained release formulation approximately monthly from
`
`the date of the second loading dose.
`
`In a further embodiment of the present invention there is provided a dosing
`
`regimen for administering paliperidone palmitate to a psychiatric patient in need of
`
`treatment comprising administering intramuscularly in the deltoid of a patient in need
`
`of treatment a first loading dose of about 75 mg-eq. of paliperidone as paliperidone
`
`palmitate formulated in a sustained release formulation on the first day of treatment;
`
`administering intramuscularly in the deltoid muscle of the patient in need of treatment a
`
`second loading dose of about 75 mg-eq of paliperidone as paliperidone palmitate
`
`formulated in a sustained release formulation on the eighth day of treatment; and
`
`administering intramuscularly in thc deltoid or gluteal muscle of the patient in need of
`
`treatment a maintenance dose of from about 25 mg-eq. to about 50 mg-eq. of
`
`paliperidone as paliperidone palmitate in a sustained release formulation on about the
`
`34th day and the 38th day of treatment.
`
`In one embodiment of the present invention there is provided a dosing regimen
`
`for administering palipcridone cstcrs to a psychiatric patient in need of treatment
`
`comprising administering intramuscularly in the deltoid a first loading dose of about
`
`150 mg-eq. of paliperidone as a paliperidone palmitate formulated in a sustained
`
`release formulation on the first day of treatment; thereafter administering
`
`intramuscularly a second maintenance dose of from about 25 mg—eq. to about 100 mg—
`
`eq of paliperidone as a paliperidone palmitate formulated in a sustained release
`
`formulation between about the 6th to 10th day of treatment; and administering
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`intramuscularly in the gluteal a maintenance dose of about 25 to about 100 mg-eq. of
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`paliperidone as a paliperidone palmitate in a sustained release formulation on between
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`about the 34th and about the 38th day of treatment.
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`In a further embodiment of the present invention there is provided a dosing
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`regimen for administering palipcridone palmitate to a psychiatric patient in need of
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`treatment comprising administering intramuscularly in the deltoid of a patient in need
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`PRD2901USNP
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`of treatment a first loading dose from about 150 mg-eq. of paliperidone as a
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`paliperidone palmitate ester in a sustained release formulation on the first day of
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`treatment; thereafter administering intramuscularly in the deltoid muscle of the patient
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`in need of treatment a maintenance dose from about 25 mg—eq. to about 100 mg—eq. of
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`paliperidone as paliperidone palmitate formulated in a sustained release formulation on
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`the eighth day of treatment; and administering intramuscularly in the deltoid or gluteal
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`muscle of the patient in need of treatment a maintenance dose of about 25 mg-eq. to
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`about 100 mg-eq. of paliperidone as paliperidone palmitate in a sustained release
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`formulation on about the 34th day and the 38th day of treatment.
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`This and other objects and advantages of the present invention may be
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`appreciated from a review of the present applications.
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`BRIEF DESCRIPTION OF THE FIGURES
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`Figure 1 shows the observed versus the population pharmaeokineties model
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`simulation for plasma paliperidone concentrations for paliperidone palmitate 150 mg
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`eq. in the deltoid on day 1, followed by 25 mg eq. in either the deltoid or gluteus on
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`days 8, 36, and 64.
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`Figure 2 shows the observed versus the population pharmacokinetics model
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`simulation for plasma paliperidone concentrations for paliperidone palmitate 150 mg
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`eq. in the deltoid on day 1, followed by 100 mg eq. in either the deltoid or gluteus on
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`days 8, 36, and 64.
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`Figure 3 shows the observed versus the population pharmacokinetics model
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`simulation for plasma paliperidone concentrations for paliperidone palmitate 150 mg
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`eq. in the deltoid on day 1, followed by 150 mg eq. in either the deltoid or gluteus on
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`days 8, 36, and 64.
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`PRD2901USNP
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`DETAILED DESCRIPTION
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`We have discovered after extensive analysis of the clinical data that paliperidone
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`palmitate due to its dissolution rate-limited absorption exhibits flip-flop kinetics, where the
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`apparent half-life is controlled by the absorption rate constant. Additionally the volume of
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`injected drug product also impacts the apparent rate constant. It was also discovered that
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`deltoid injections result in a faster rise in initial plasma concentration, facilitating a rapid
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`attainment of potential therapeutic concentrations. Consequently, to facilitate patients’
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`attaining a rapid thcrapcutic concentration of paliperidone it is preferred to provide the
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`initial loading dose of paliperidone palmitate in the deltoids. The loading dose should be
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`from about 100 mg-eq. to about 150 mg-eq. of paliperidone provided in the form of
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`paliperidone palmitate. After the first or more preferably after the second loading dose
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`injection patients will be approaching a steady state concentration of paliperidone in their
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`plasma and may be injected in either the deltoid or the gluteal muscle thereafter. However,
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`it is preferred that the patients receive further injections in the gluteal muscle.
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`In view of these discoveries the recommended dosing regimen for patients to attain
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`a therapeutic plasma level of paliperidone is for patients to receive the first dose of
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`paliperidone palmitate on day l of treatment, followed by a second dose between days 6 to
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`10 of treatment, then a third dose between days 34 to 38 of treatment or monthly ::7 days
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`after the second dose. More preferably the patients will be administered a first dose on day
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`l, a second dose on day 8 and a third dose on or about day 36 of treatment or
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`approximately monthly ::3 days after the second dose. The first two doses will preferably
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`be injected in the deltoid muscle. Thereafter paliperidone palmitate will be administered
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`by injection approximately once a month (e.g. monthly ::7days or approximately once
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`every four weeks) thcrcaftcr. To assure that a potential therapeutic plasma level of
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`paliperidone is attained at least a first loading dose of 150 mg-eq of paliperidone as a
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`paliperidone palmitate ester should be administered on day one of treatment. Preferably
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`the first two doses will be loading dose of between from about 100 mg-eq. to about 150
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`mg—eq. of paliperidone as a paliperidone palmitate ester to assure that a potential
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`therapeutic plasma level of paliperidone is attained by the patient. The subsequent doses
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`thereafter will drop to a therapeutic maintenance dose of from about 25 mg-eq. to 150 mg-
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`eq. per month (i7 days). Preferably the maintenance dose will be from about 25mg eq. to
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`about 100 mg eq; more preferably the maintenance dose will be from about 25mg eq. to
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`PRD2901USNP
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`about 75 mg eq; and most preferably the maintenance dose initially will be about 50 mg
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`eq., or more preferably the maintenance dose initially will be about 75 mg eq. which may
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`be administered intramuscularly into the deltoid or gluteal muscle, but more preferably
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`will be administered in the gluteal muscle. Those of ordinary skill in the art will
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`understand that the maintenance dose may be titrated up or down in view of the patients
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`condition (response to the medication and renal fiinction).
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`Since paliperidone is mainly eliminated through the kidneys, patients with renal
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`impairment will have a higher total exposure to paliperidone after i.m. injections of
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`paliperidone palmitate. For patients with renal impairment it would desirable to adjust the
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`loading doses to account for the increased exposure levels of patients with renal
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`impairment. For patients with mild renal impairment the loading doses should be reduced
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`to 75 mg-eq. for the first two loading doses. The maintenance doses should range from
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`about 25 mg-eq. to about 75 mg-eq. and more preferably with range from about 25 mg-eq.
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`to about 50 mg-eq. The doses would be administered on day 1 of treatment, followed by a
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`second dose between days 6 to 10 of treatment, then a third dose between days 34 to 38 of
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`treatment. More preferably the patients will be administered a first dose on day 1, a
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`second dose on day 8 and a third dose on day 36 of treatment. The first two doses will
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`preferably be injected in the deltoid muscle. Thereafter paliperidone palmitate will be
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`administered by injection approximately once a month (e.g. one a month :7 days or once
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`every four weeks) thereafter. For the purpose of this patent app lieation renal fimction is
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`estimated by glomerular filtration rate (GFR) usually measured by the ereatinine clearance
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`(best calculated from a 24-hour urine collection). Creatine clearance may be estimated by
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`the Cockcroft and Gault method based on serum creatinine concentration, as described in
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`Prediction of creatinine clearance from serum creatinine. Nephron 1976; vol 16. pages 31-
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`41. Patients with mild renal impairment have a ereatinine clearance of 50 to <80
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`mL/minute.
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`It is recommended that the second initiation dose of paliperidone palmitate be
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`given about one week (6-10 days) after the first dose. To avoid a missed dose, patients
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`may be given the second dose 2 days before or after the one—week time point. Similarly,
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`the third and subsequent injections after the initiation regimen are recommended to be
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`given monthly. To avoid a missed monthly dose, patients may be given the injection up
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`to 7 days before or after the monthly time point.
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`After initiation, the recommended injection cycle of paliperidone palmitate is
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`monthly. If less than 6 weeks have elapsed since the last injection, then the previously
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`stabilized dose should be administered as soon as possible, followed by injections at
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`monthly intervals.
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`If more than 6 weeks have elapsed since the last injection, reinitiation with the
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`same dose the patient was previously stabilized to should be resumed in the following
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`manner: 1) a deltoid injection as soon as practically possible, followed by 2) another
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`deltoid injection one week later, and 3) resumption of either deltoid or gluteal dosing at
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`monthly intervals.
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`If more than 6 months have elapsed since the last injection, it is recommended
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`to re-initiate dosing as described above.
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`Additionally, in this patient population needle length and BMI index are two
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`related variables that need to be considered to assure patients attain therapeutic
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`concentration of paliperidone in the desired time frame. Patients with high BMI had lower
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`plasma concentration of paliperidone and a lessened treatment response. The lower initial
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`plasma concentration in high BMI patients was likely due to unintended partial or
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`complete injection into adipose tissue, instead of deep injection into muscle. However,
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`once steady-state plasma concentration are attained BMI no longer influenced plasma
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`concentrations or clinical efficacy. From these observations it was determined that for
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`patients weighing <90 kg (< 200 lb) a l—inch needle will be of adequate length to use in
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`injections to reach the muscle tissue for deltoid injections with preferably a 23 gauge
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`needle. However, for patients with high BMIs, 290 kg (2 200 lb) a 1.5-inch needle should
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`be used for deltoid injections. For gluteal muscle injections a 1.5-inch needle should be
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`used. Preferably the 1.5-inch needle will be a 22-gauge needle.
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`Paliperidone esters are psychotic agents belonging to the chemical class of
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`benzisoxazole derivatives, which contains a racemic mixture of (+)- and (-)-
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`paliperidone, which are described in US Patent 5,254,556 (incorporated herein by
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`reference). The chemical name for paliperidone palmitate is (i)-3-[2-[4-(6-fluoro-l ,2-
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`benzisoxazol-3 -yl)-1 -piperidinyl] ethyl] -6,7, 8 ,9-tetrahydro-2-methyl-4-oxo-4H—
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`pyrido[1,2—a]pyrimidin—9—yl hexadecanoate. The structural formula is:
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