`
`ABSTRACT
`
`The present disclosure provides methods for evaluating daily ammonia exposure based
`
`on a single fasting ammonia blood level nieasurement, as well as methods that utilize this
`
`technique to adjust the dosage ofa nitrogen scavenging drug, determine whether to administer a
`
`nitrogen scavenging drug, and treat nitrogen retention disorders.
`
`':'9532—fi[H'J3.L'Fi{]li'l_EGA]_227l-i9(l5_]
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`EX.
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`1 8
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`1 of 210
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`
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`Electronic Acknowledgement Receipt
`
`Application Number:
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`13417137
`
`International Application Number:
`
`Confirmation Number:
`
`Title of Invention:
`
`MEFHODS OF THERAPEUTIC MONFTORING OF NITROGEN SCAVENGING
`DRUGS
`
`First Named lnventorlfipplicant Name:
`
`Bruce SCHARSCHMIDT
`
`Customer Number:
`
`34055
`
`Filer:
`
`Patrick D. Morrisz’Col|een Kirchner
`
`Filer Authorized By:
`
`Patrick D. Morris
`
`Receipt Date:
`
`09—MAFi—2012
`
`Filing Date:
`
`Time Stamp:
`
`20:28:09
`
`Application Type:
`
`Utility under 35 USC 11 Ha}
`
`Payment information:
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`Submitted with Payment
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`Payment Type
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`Payment was successfully received in RAM
`RAM confirmation Number
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`Deposit Account
`Authorized User
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`$1025
`6954
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`502586
`
`The Director ofthe USPTO is hereby authorized to charge indicated fees and credit any overpayment as follows:
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`Charge any Additional Fees required under 37 CPR. Section 1.16 (National application filing, search, and examination fees}
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`Document Description
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`Transmittal of New Application
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`Transmittaipdf
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`File Size{Byles}{
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`1857?
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`ldrl? I Hm ¥.ri«I?'.‘o£ .1 ‘JJ 9(|')NJlrri [Wu WW.
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`We rnings:
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`Info rmation:
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`Warnings:
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`Information:
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`Warnings:
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`Information:
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`Warnings:
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`Info rrnation:
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`U5_5pecification.pdf
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`E.2wb2?l.id-I-l:n.'4ai!ic’;rrJ-5:1?I3r.'LI'.'J‘)eiI-i
`is In: H
`
`Multipart DescriptionlPDF files in .zip description
`
`Specification
`
`Claims
`
`Drawings-only black and white line drawings
`
`Petition to make special based on Age}
`Health
`
`iPetitiontoMa keSpecial.pdf
`
`l.NIII0“1.ihI'iJ Il|II'|2'i‘)Ji|.Ed)EL‘P| .iEI'Ji.ilJi?|J9
`ti Illlif
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`Fee Worksheet {SE06}
`
`fee-infopdf
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`3 of 210
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`This Acknowledgement Receipt evidences receipt on the noted date by the USPTO of the indicated documents,
`characterized by the applicant, and including page counts, where applicable. It serves as evidence of receipt similar to a
`Post Ca rd, s described in MPEP 503.
`
`New Applications Under 35 U.S.C. 111
`Ifa new application is being filed and the application includes the necessary components for a filing date (see 37 CFR
`1.53lb‘,|-{dl and MPEP 506), a Filing Receipt (37 CFR 1.54) will be issued in due course and the date shown on this
`Acknowledgement Receipt will establish the filing date of the application.
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`National Stage of an International Application under 35 U.S.C. 371
`If a timely submission to enter the national stage of an international application is compliant with the conditions of 35
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`national stage submission under 35 U.S.C. 311 will be issued in addition to the Filing Receipt, in due course.
`
`New International Application Filed with the USPTO as a Receiving Office
`lfa new international application is being filed nd the international application includes the necessary components for
`an international filing date (see PCT Article 11 and MPEP 1810), a Notification of the International Application Number
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`4 of 210
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`
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`Attorney Rel‘. 79S32.8ll03.US(I2
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`Vlfhat is claimed is:
`
`I.
`
`A method for determining whether to increase a dosage ofa nitrogen scavenging
`
`drug in a subject currently receiving the nitrogen scavenging dmg, comprising:
`
`a) measuring a fasting blood ammonia level for the subject; and
`
`b) comparing the fasting blood ammonia level to the upper limit of normal for blood
`
`ammonia level to determine whether to increase the dosage of a nitrogen scavenging drug,
`
`wherein the dosage needs to be increased if the fasting blood ammonia level is greater than half
`
`the upper limit of nonrial for blood ammonia level.
`
`2.
`
`A method for determining whether to administer a nitrogen scavenging drug to a
`
`subject having a nitrogen retention disorder comprising:
`
`a) measuring a fasting blood ammonia level For the subject; and
`
`b) comparing the fasting blood ammonia level to the upper limit of normal for blood
`
`ammonia level to determine whether to administer a nitrogen scavenging drug to the subject,
`
`wherein a nitrogen scavenging drug needs to be administered to the subject if the fasting blood
`
`ammonia level is greater than half the upper limit of normal for blood ammonia level.
`
`3.
`
`A method of treating a subject with a nitrogen retention disorder who has
`
`previously been administered a nitrogen scavenging drug comprising:
`
`a) measuring a fasting blood ammonia level for the subject; and
`
`b) comparing the fasting blood ammonia level to the upper limit of normal for blood
`
`ammonia level and administering an increased dosage of the nitrogen scavenging drug if the
`
`fasting blood ammonia level is greater than half the upper limit of normal for blood ammonia
`
`level.
`
`4.
`
`The method of claim 1. further comprising:
`
`c") administering an increased dosage of the nitrogen scavenging drug if the need exists.
`
`5.
`
`The method of any of claims 13, wherein the nitrogen retention disorder is
`
`selected from the group consisting of a urea cycle disorder and hepatic encephalopathy.
`
`6.
`
`The method of any of claims 1-3, wherein the nitrogen scavenging drug is a PAA
`
`prodrug.
`
`7.
`
`The method of claim 6, wherein the FAA prodrug is selected from the group
`
`consisting of glyceryl tri—[4—phenylbutyrate] (HPNFIOO). phenylbutyric acid (PBA), sodium PBA
`
`(NaPBA), and a combination of two or more of HPN-100, PBA, and NaPBA.
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`'I9532—fi[l'l'J3 .USfl l.I'l_F.GA].2'."_i' l —t9{l5 .]
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`5 of 210
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`Attorney Rel‘. 79S32.8{|03.US(I2
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`8.
`
`The method of any of claims ]—3, wherein the nitrogen scavenging chug is sodium
`
`benzoate.
`
`9.
`
`The method of claim 3 or 4, wherein administering an increased dosage of the
`
`nitrogen scavenging dmg produces a normal average daily ammonia level in the subject.
`
`10.
`
`The method of any of claims 1-3, further comprising the step of determining an
`
`upper limit of normal for blood ammonia level for the subject prior to step (b).
`
`11.
`
`The method of any of claims 1-3, wherein the upper limit of l"lDlT[1E1l blood
`
`ammonia level is 35 |.imo1!L.
`
`12.
`
`The method of claim 6, further comprising:
`
`c") measuring urinary PAGN excretion; and
`
`e) determining an effective dosage of the PAA prodrug based on a mean conversion of
`
`PAA prodrug to urinary PAGN of 60-75%.
`
`'I'}532—fi[H'J_l .['S{llfL.EGA].2'.’J I 49135.]
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`6 of 210
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`
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`Figure 1
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`
`9 of 210
`
`
`
`Electronic Acknowledgement Receipt
`
`Application Number:
`
`13417137
`
`International Application Number:
`
`Confirmation Number:
`
`Title of Invention:
`
`MEFHODS OF THERAPEUTIC MONFTORING OF NITROGEN SCAVENGING
`DRUGS
`
`First Named lnventorlfipplicant Name:
`
`Bruce SCHARSCHMIDT
`
`Customer Number:
`
`34055
`
`Filer:
`
`Patrick D. Morrisz’Col|een Kirchner
`
`Filer Authorized By:
`
`Patrick D. Morris
`
`Receipt Date:
`
`09—MAFi—2012
`
`Filing Date:
`
`Time Stamp:
`
`20:28:09
`
`Application Type:
`
`Utility under 35 USC 11 Ha}
`
`Payment information:
`
`Submitted with Payment
`
`Payment Type
`
`Payment was successfully received in RAM
`RAM confirmation Number
`
`Deposit Account
`Authorized User
`
`Deposit Account
`
`$1025
`6954
`
`502586
`
`The Director ofthe USPTO is hereby authorized to charge indicated fees and credit any overpayment as follows:
`
`Charge any Additional Fees required under 37 CPR. Section 1.16 (National application filing, search, and examination fees}
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`Document
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`Transmittal of New Application
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`ldrl? I Hm ¥.ri«I?'.‘o£ .1 ‘JJ 9(|')NJlrri [Wu WW.
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`Information:
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`U5_5pecification.pdf
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`E.2wb2?l.id-I-l:n.'4ai!ic’;rrJ-5:1?I3r.'LI'.'J‘)eiI-i
`is In: H
`
`Multipart DescriptionlPDF files in .zip description
`
`Specification
`
`Claims
`
`Drawings-only black and white line drawings
`
`Petition to make special based on Age}
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`iPetitiontoMa keSpecial.pdf
`
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`ti Illlif
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`Electronic Patent Application Fee Transmittal
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`Title of Invention:
`
`MEFHODS OF THERAPEUTIC MONiTORlNG OF NITROGEN SCAVENGING
`DRUGS
`
`First Named lnventormpplica nt Name:
`
`Bruce SCHARSCHNIIDT
`
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`
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`
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`211 1
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`1
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`2311
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`1
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`310
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`310
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`‘I25
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`2203
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`1
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`225
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`225
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`r-roiaeinau (circa;
`,:.,.,,....,._.........,....i......g...mm.,.; gyms 0.-.5._.m.
`Description : Petition to make special based on AgeI‘Health
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`UNDER 3? CFR 1.1 D2(c)(‘l)
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`7
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`2012 D3 D9
`
`Attorney Docket
`Number (opfionai)
`
`79533-3093-U302
`
`.
`Art Unit
`
`First Named
`Inventor
`
`Bruce Scharschrnidt
`
`.
`Examiner
`
`Title of Invention
`
`METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING DRUGS
`
`Attention: Office of Petitions
`
`An application may be made special for advancement of examination upon filing of a petition showing that the applicant is 5
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`EFSWe|:I1.Cl.13
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`16 of 210
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`Attorney Rel‘. 79S32.8003.US(I2
`
`METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING
`
`DRUGS
`
`RELATED APPLICATIONS
`
`[0001] The present application claims the benefit ofU.S. Provisional Application No.
`
`6lf564.668. filed November 29. 2011. and U.S. Provisional Application No. 61/541100. filed
`
`September 30, 2011. the disclosures of which are incorporated by reference herein in their
`
`entirety, including drawings.
`
`BACKGROUND
`
`[0002] Nitrogen retention disorders associated with elevated ammonia levels include urea cycle
`
`disorders (UCDS) and hepatic encephalopathy (HE).
`
`[0003] UCDS include several inherited deficiencies of enzymes or transporters necessary for
`
`the synthesis of urea from ammonia, including enzymes involved in the urea cycle. The area
`
`cycle is depicted in Figure 1. which also illustrates how certain ammonia—scavenging drugs act to
`
`assist in elimination of excessive. ammonia. With reference to Figure l. N—acetyl glutamine
`
`synthetase (NAGS)-derived N-acetylglutamate binds to carbamyl phosphate synthetase (CPS).
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`which activates CPS and results in the conversion of ammonia and bicarbonate to carbamyl
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`phosphate.
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`In turn, carbamyl phosphate reacts with ornithine to produce citrulline in a 1'eacti0n
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`mediated by ornithine transcarbamylase (OTC). A second molecule of waste nitrogen is
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`incorporated into the urea cycle in the next reaction. mediated by arginosuccinate synthetase
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`(A33), in which citrulline is condensed with aspartic acid to form argininosuccinic acid.
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`Argininosuccinic acid is cleaved by argininosuccinic lyase (ASL) to produce arginine and
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`fumarate.
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`In the final reaction of the urea cycle. arginase (ARG) cleaves arginine to produce
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`omithine and urea. Of the two atoms of nitrogen incorporated into urea, one originates from free
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`ammonia (N HI) and the other from aspartate. UCD individuals born with no meaningful
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`residual urea synthetic capacity typically present in the first few days oflife (neonatal
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`presentation). Individuals with residual function typically present later in childhood or even in
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`adulthood, and symptoms may be precipitated by increased dietary protein or physiological
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`stress {e.g.. intercunent illness}.
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`[0004] Hepatic encephalopathy (HE) refers to a spectrum of neurologic signs and symptoms
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`believed to result from hyperammonernia, which frequently occur in subjects with cirrhosis or
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`certain other types of liver disease. Subjects with HE typically show altered mental status
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`ranging from subtle changes to coma, features similar to subjects with UCDs.
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`[0005] Subjects with nitrogen retention disorders whose ammonia levels andfor symptoms are
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`not adequately controlled by dietary restriction of protein andfor dietary supplements are
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`generally treated with nitrogen scavenging agents such as sodium phenylbutyrate (N aPBA,
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`approved in the United States as BUPHENYL® and in Europe as AMMONAPS®) or sodium
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`benzoate. These are often referred to as alternate pathway drugs because they provide the body
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`with an alternate pathway to urea for excretion of waste nitrogen (Brusilow 1930: Brusilow
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`1991). NaPBA is a phenylacetic acid (PAA) prodrug. Another nitrogen scavenging dnlg
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`currently in development for the treatment of nitrogen retention disorders is glyceryl tri—[4—
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`pheny1butyrate](HPN~100), which is described in Us. Patent No. 5,963,979.
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`I-IPN~]C}0, which is
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`commonly referred to as GT4P or glycerol PBA, is a prodrug of PBA and a pre—prodrug of PAA.
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`[0006] HPN—lOD and N:—1PBA share the same general mechanism of action: PBA is converted
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`to PAA via beta oxidation. and FAA is conjugated enzymatically with glutamine to form
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`phenylacetylglutamine (PAGN). which is excreted in the urine. The structures of PBA. PAA,
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`and PAGN are set forth below.
`
`‘- “’\'“~”’"“-cos-Na‘
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`pnenyihtity rate
`
`r'
`
`.
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`Phenviacetéc acid
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`N83
`
`H
`
`<2
`
`/my
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`Pheaviasetvlg-tutamine
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`[0007] The clinical benefit of NaPBA and I-1PN—l0U with regard to nitrogen retention disorders
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`derives from the ability of PAGN to effectively replace urea as a vehicle for waste nitrogen
`
`excretion andfor to reduce the need for urea synthesis (Brusilow 1991; Brusilow 1993). Because
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`each glutamine contains two molecules of nitrogen, the body rids itself of two waste nitrogen
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`atoms for every molecule of PAGN excreted in the urine. Therefore, two equivalents of nitrogen
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`are removed for each mole of PAA converted to PAGN. PAGN represents the predominant
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`terminal metabolite, and one that is stoichiometrically related to waste nitrogen removal. a
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`measure of efficacy in the case of nitrogen retention states. The difference between HPN-100
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`and NaPBA with respect to metabolism is that HPN-100 is a triglyceride and requires digestion,
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`presumably by pancreatic lipases, to release PBA (McGuire 2010).
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`[0008]
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`In contrast to NaPBA or HPN-100, sodium benzoate acts when benzoic acid is
`
`combined enzymatically with glycine to form hippuric acid. For each molecule of hippuric acid
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`excreted in the urine, the body rids itself of one waste nitrogen atom.
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`[0009] Methods of determining an effective dosage of PAA prodrugs such as NaPBA or HPN—
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`I00 for a subject in need of treatment for a nitrogen retention disorder are described in
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`W009/1 134460 and W010/025303. Daily ammonia levels. however. may vary greatly in a
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`subject. This can lead to overestimation by the physician of the average daily ammonia levels.
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`which may result in overtreatment. Thus, there is a need in the art for improved methods for
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`PAA prodrug dose determination and adjustment based on ammonia levels in subjects with
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`nitrogen retention disorders such as UCDs or HE.
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`SUMMARY
`
`[0010] Provided herein in certain embodiments are methods for determining whether to
`
`increase a dosage of a nitrogen scavenging drug in a subject with a nitrogen retention disorder by
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`measuring a fasting blood ammonia level and comparing the fasting blood ammonia level to the
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`upper limit of normal (ULN) for blood ammonia. where a fasting blood ammonia level that is
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`greater than half the ULN for blood ammonia indicates that the dosage needs to be increased.
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`In
`
`certain embodiments. the. nitrogen retention disorder is a UCD or HE.
`
`In certain embodiments,
`
`the nitrogen scavenging drug is HPNJUU. PBA, NaPBA, sodium benzoate, or any combination
`
`thereof(i.e., any combination of two or more of HPN—lU0. PBA. NELPBA).
`
`In certain
`
`embodiments. the ULN is around 35 p.mol/L or 59 j,I.g1'mL.
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`In certain embodiments. the methods
`
`include an additional step of administering an increased dosage of the nitrogen scavenging drug
`
`if the need exists, and in certain of these embodiments administration of the nitrogen scavenging
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`drug produces a normal average daily ammonia level in the subject.
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`In certain embodiments
`
`wherein a determination is made to administer an increased dosage of nitrogen scavenging drug
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`and wherein the nitrogen scavenging drug is a FAA prodrug, the methods include an additional
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`step of measuring urinary PAGN excretion and determining an effective dosage of the FAA
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`prodmg based on a mean conversion of PAA prodrug to urinary PAGN of 60-75%.
`
`[001]] Provided herein in certain embodiments are methods for determining whether to
`
`administer a nitrogen scavenging drug to a subject with a nitrogen retention disorder by
`
`measuring :1 fasting blood ammonia level and comparing the fasting blood ammonia level to the.
`
`ULN for blood ammonia. where a fasting blood ammonia level that is greater than half the ULN
`
`for blood ammonia indicates that the nitrogen scavenging drug needs to be administered.
`
`In
`
`certain embodiments, the nitrogen retention disorder is a UCD or HE.
`
`In certain embodiments,
`
`the nitrogen scavenging drug is HPN—l00, PBA. NaPBA. sodium benzoate, or any combination
`
`thereof(i.e_, any combination of two or more of HPN—lU0, PBA, NaPBA).
`
`In certain
`
`embodiments. the ULN is around 35 uu1o1lL o1'59 ug/mL.
`
`In certain embodiments, the methods
`
`include an additional step of administering a nitrogen scavenging drug if the need exists, and in
`
`certain of these embodiments administration of the nitrogen scavenging drug produces a normal
`
`average daily ammonia level in the subject.
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`In certain embodiments wherein a determination is
`
`made to administer a nitrogen scavenging drug and wherein the nitrogen scavenging drug is a
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`PAA prodrug. the methods further include a step of determining an effective initial dosage of the
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`PAA prodru g by determining a target urinary PAGN output based on a target nitrogen output and
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`calculatin g an effective initial dosage that results in the. target urinary PAGN output based on a
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`mean conversion of PAA prodrug to urinary PAGN of 60-75%.
`
`In certain embodiments, the
`
`methods include a step of administering the calculated effective initial dosage.
`
`[0012] Provided herein in certain embodiments are methods for treating a nitrogen retention
`
`disorder in a subject who has previously been administered a nitrogen scavenging drug by
`
`measuring a fasting blood ammonia level, comparing the fasting blood ammonia level to the
`
`ULN for blood ammonia, and administering an increased dosage of the nitrogen scavenging drug
`
`if the fasting ammonia level is greater than half the ULN for blood ammonia.
`
`In certain
`
`embodiments, administration of an increased dosage of the nitrogen scavenging drug produces a
`
`normal average daily ammonia level in the subject.
`
`In certain embodiments, the nitrogen
`
`retention disorder is a UCD or HE.
`
`In certain embodiments, the nitrogen scavenging drug is
`
`HPN -100. PBA, NaPBA. sodium benzoate. or any combination thereof (i.e., any combination of
`
`two or more of HPN—l00, PBA, NaPBA).
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`In certain embodiments, the ULN is around 35
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`urnolfL or 59 tLgfmL.
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`In certain embodiments wherein the nitrogen scavenging drug is a PAA
`
`prodtug, the methods include an additional step of measuring urinaiy PAGN excretion and
`
`determining an effective dosage of the FAA prodru g based on a mean conversion of PAA
`
`prodrug to urinary PAGN of 60—75%.
`
`In certain embodiments. the methods include a step of
`
`administering the calculated effective. dosage.
`
`BRIEF DESCRIPTION OF DRAWINGS
`
`[0013] Figure l: The urea cycle and how certain nitrogen-scavenging drugs may assist in
`
`elimination of excessive ammonia.
`
`[0014]
`
`Figure 2: Relationship between fasting ammonia and average ammonia UCD patients.
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`[0015] Figure 3: Venous blood ammonia values over 24 hours in (A) adult and (B) pediatric
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`UCD patients.
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`DETAILED DESCRIPTION
`
`[0016] The following description of the invention is merely intended to illustrate. various
`
`embodiments of the invention. As such, the specific modifications discussed are not to be
`
`construed as limitations on the scope of the invention. It will be apparent to one skilled in the art
`
`that various equivalents, changes, and modifications may be made without departing from the
`
`scope of the invention. and it is understood that such equivalent embodiments are to be included
`
`herein.
`
`[0017]
`
`In subjects with a nitrogen retention disorder. the desired effect of treatment with a
`
`nitrogen scavenging drug is control of blood ammonia level. Control of blood ammonia level
`
`generally refers to amtnonia values within the normal range and avoidance of hyperamrnonemic
`
`crises. which are often defined in the art as transient ammonia values exceeding 100 ttmol/L or
`
`178 pg/mL accompanied by clinical signs and symptoms of hyperammonemia. Dosing of
`
`nitrogen scavenging drugs is usually based upon clinical assessment and measurement of
`
`ammonia. However, assessment of treatment effect and interpretation of ammonia levels is
`
`confounded by the fact that individual ammonia values vary several—fold over the course of a day
`
`and are impacted by timing of the blood draw in relation to the last meal and dose of drug (see,
`
`e.g., Lee ZOIO: Lichter—Konecki 201 l; Diaz 201 I}.
`
`[0018] A random ammonia value obtained during an outpatient visit may fail to provide a
`
`reliable measure of a subject's status and the drug effect. For example, basing treatment on a
`
`blood sample taken after eating :1 meal might overestimate average daily ammonia level and
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`result in overtreatment. Conversely. basing treatment on a blood sample taken after drug
`
`administration might underestimate average daily arnmonia level and result in undertreatment. A
`
`fasting ammonia level at or near the ULN might be tak