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`as) United States
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`a2) Patent Application Publication co) Pub. No.: US 2012/0022157 Al
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` Scharschmidt (43) Pub. Date: Jan. 26, 2012
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`US 20120022157A1
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`(54) DOSING AND MONITORING PATIENTS ON
`NITROGEN-SCAVENGING DRUGS
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`(75)
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`Inventor:
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`(73) Assignee:
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`Bruce Scharschmidt, South San
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`Francisco, CA (US)
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`;
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`UCYCLYD PHARMA,INC,
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`Scottsdale, AZ (US)
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`(21) Appl. No.:
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`13/061,509
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`(22) PCT Filed:
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`(86) PCT No.:
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`Aug.27, 2009
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`PCT/US09/55256
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`§ 371 (c)(1),
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`(2), (4) Date:
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`Jun. 15, 2011
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`Related U.S. Application Data
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`(63) Continuation-in-part of application No. PCT/US09/
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`30362, filed on Jan. 7, 2009, Continuation-in-part of
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`application No. 12/350,111, filed on Jan. 7, 2009.
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`(60) Provisional application No. 61/093,234,filed on Aug.
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`29, 2008, provisional application No. 61/093,234,
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`filed on Aug. 29, 2008.
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`Publication Classification
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`(51)
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`Int. Cl.
`AGIK 31/216
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`AG6IP 3/00
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`GOIN 33/00
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`AGIP 13/12
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`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
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`(52) US. CM wee 514/533; 514/532; 73/61.41
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`ABSTRACT
`(57)
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`The invention provides a method for determining a dose and
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`dosing schedule, and making dose adjustments of patients
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`taking PBA prodrugsas nitrogen scavengersto treat nitrogen
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`retention states, including ammonia accumulation disorders
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`as well as chronic renal failure, by measuring urinary excre-
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`tion of phenylacetylglutamine and/ortotal urinary nitrogen.
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`The invention provides methodsto select an appropriate dos-
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`age of a PBA prodrug basedon the patient’s dietary protein
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`intake, or based on previous treatments administered to the
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`patient. The methodsare applicable to selecting or modifying
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`a dosing regimen for a subject receiving an orally adminis-
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`tered waste nitrogen scavenging drug, and to monitoring
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`patients receiving such drugs.
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`Page 1 of 48
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`Horizon Exhibit 2012
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`Par v. Horizon
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`IPR2017-01768
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`Page 1 of 48
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`Horizon Exhibit 2012
`Par v. Horizon
`IPR2017-01768
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`Patent Application Publication
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`Jan. 26, 2012 Sheet 1 of 17
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`Patent Application Publication
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`Jan. 26, 2012 Sheet 2 of 17
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`US 2012/0022157 Al
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`US 2012/0022157 Al
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`Patent Application Publication
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`Jan. 26, 2012 Sheet 4 of 17
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`Jan. 26,2012 Sheet 5 of 17
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`US 2012/0022157 Al
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`Jan. 26, 2012 Sheet 6 of 17
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`Jan. 26,2012 Sheet 7 of 17
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`US 2012/0022157 Al
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`UP1204-002: Blood Metabolite Concentrations
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`Vs. Time in Healthy Adults*
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`Analyte=PBA
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`* Shows BID dosing fram days 8-15.
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`Plasma PBAlevels returned to near predose
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`UP1204-002: Blood Metabolite Concentrations
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`Vs. Time in Palients With Cirrhosis (Childs-Pugh C)
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`Analyte=PBA
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`steady-state with BID dosing
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`Figure 8a
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`20 —o- HPN-100fp29
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`Page 11 of 48
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`9500
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`Figure 8b
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`Jan. 26, 2012 Sheet 11 of 17
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`U-PAGNand HPN Dose 20-aepeeeea 16000000
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`BUPHENYL®|_HPN-100
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`38.4 +/- 19.6|26.1 +/- 10.3
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`Figure 9
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`Cumulative Ammonia Concentration TN-AUC
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`Ammonia(umol*h/L} nERR
`oS‘N YY _
`
`nmoO
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`0-12Hr
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`12-24Hr
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`Figure 10
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`[s9'9]{92°81zoog——
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`ITaansey
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`(q/jowr?)
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`ONVNI-NdH
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`ONVNI-dnd
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`[2°21][S94]zoog——
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`[ren]Lyetlpoos——
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`[2°21][gbLb]e002--—
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`[6st][est]Zool
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`(q/jown)
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`[sg'a]{92°9]Loos——
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`2980p[NdH}[dnalJoelqns
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`Patent Application Publication
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`Ammonia(TN-AUC) After 7 Days of Treatment
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`with BUPHENYL and HPN-100
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`80~
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`= 60
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`S eSe
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`40
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`Sedmasnecfe oro eehcccsnncereceeeceeseesfecceeecet tests
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`=
`HPN-100
` (38.4+/-19.6
`B
`Mean
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`26.1+-/-10.3
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`20-
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`BUPHENYL”
` HPN-100
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`‘Figure 12
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`EHN INWNL
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`US 2012/0022157 Al
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`US 2012/0022157 Al
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`Jan. 26, 2012
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`DOSING AND MONITORING PATIENTS ON
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`NITROGEN-SCAVENGING DRUGS
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`CROSS-REFERENCE TO RELATED
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`APPLICATIONS
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`[0001] This application is a continuation in part of U.S.
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`Nonprovisional patent application Ser. No. 12/350,111, filed
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`Jan. 7, 2009 which is pending, and a continuation in part of
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`International Application No. PCT/US08/30362, filed Jan. 9,
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`2009, each of which claims benefit of priority to U.S. Provi-
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`sional Application Ser. No. 61/093,234, filed Aug. 29, 2008,
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`each of which is incorporated herein by reference in its
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`entirety. This application is also related to the U.S. provi-
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`sional patent application entitled “Treating special popula-
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`tions having liver disease with nitrogen-scavenging com-
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`pounds,” naming Sharron Gargosky as inventor, Ser. No.
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`61/048,830,filed on Apr. 29, 2008.
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`TECHNICAL FIELD
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`[0002] This invention relates to treatment of patients with
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`nitrogen retention states,
`including urea cycle disorders
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`(UCDs), cirrhosis complicated by hepatic encephalopathy
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`(HE) and chronic renal failure (CRF), using administered
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`compoundsthat assist in elimination of waste nitrogen from
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`the body. The compounds can be orally administered small-
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`molecule drugs, and the invention provides methods for
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`delivering such compoundsandselecting suitable dosages for
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`a patient as well as adjusting dosages and monitoring effec-
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`tiveness of a treatment. As depicted in FIG. 1a, inherited
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`disorders (e.g., UCDs) and acquired disorders(e.g. cirrhosis,
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`typically with portal systemic shunting, complicated by HE)
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`involving the liver which impair the normally efficient clear-
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`ance of ammonia from the portal circulation and conversion
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`to urea via the urea cycle, depicted in FIG. 18, result in
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`elevated levels in the blood of ammonia, a potent neurotoxin.
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`CRF, while associated in someinstances with mildly elevated
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`levels of ammonia, (Deferrari, Kid Int. 1980; 20:505), results
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`in retention of other nitrogenous waste products normally
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`excreted in the urine, in particular urea, the blood levels of
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`which are commonly usedto assess renal function.
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`[0003] Restriction of dietary protein (i.e. intake of dietary
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`nitrogen) is commonly used in the management of each of
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`these nitrogen retention states, to avoid accumulation of
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`ammonia or metabolic products containing ammonia, e.g.,
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`urea. References herein to ammonia and ammonia scaveng-
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`ing refer primarily to treating UCDs and HEand conditions
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`that emulate UCDs, although the terms ammonia scavenging
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`and waste nitrogen scavenging are used interchangeably.
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`BACKGROUND ART
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`[0004] Drug dosing is usually based upon measurement of
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`blood levels of the active drug species in conjunction with
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`clinical assessment of treatment response. However,
`the
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`present invention is based on evidence that for certain pro-
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`drugs of phenylacetic acid (PAA), measuring the bloodlevel
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`of the prodrug (e.g. PBA) or of PAA formed from it is unre-
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`liable in assessing drug effect: drug levels in the blood do not
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`correlate with efficacy in this case. In addition, assessment of
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`treatmenteffect by measuring levels of ammonia in the blood
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`in UCD patients is also potentially unreliable. Individual
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`ammonia level measurements vary several-fold over the
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`course of a day for a given patient, and withdrawing multiple
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`blood samples under carefully controlled conditions over an
`Page 19 of 48
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`extended period of time is clinically impractical as a way to
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`monitor a treated patient. The variability in blood ammonia
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`levels reflects the fact that ammonia levels in UCD patients
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`are affected by various factors including dietary protein and
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`timing in relation to meals, such that any individual value fails
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`to provide a reliable measure of how much ammonia the drug
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`is mobilizing for elimination; 1.e. drug effect. The invention
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`demonstrates that prodrugs of phenylbutyric acid (PBA)
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`behave similarly to sodium PBA, in that measuring PBA
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`levels is unreliable for assessing their effectiveness. This
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`invention provides a novel method for dosing in patients with
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`nitrogen retention states, in particular patients with liver dis-
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`ease and clinical manifestations of hepatic encephalopathy
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`and patients with UCDs. It is particularly applicable to pro-
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`drugs that liberate or are metabolized to form phenylacetic
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`i.e., prodrugs of PAA, and those prodrugs that are
`acid,
`metabolized to form PBA.
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`[0005] Hepatic encephalopathy (HE)refers to a reversible
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`spectrum ofneurologic signs and symptoms which frequently
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`occurin patients with cirrhosis or certain other types of liver
`disease.
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`[0006] Urea cycle disorders (UCDs) comprise several
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`inherited deficiencies of enzymes or transporters necessary
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`for the synthesis of urea from ammonia. The urea cycle is
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`depicted in FIG. 15, whichalsoillustrates how certain ammo-
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`nia-scavenging drugsact to assist in elimination of excessive
`ammonia. UCDsinclude inherited conditions associated with
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`insufficient function of any one of several ammonia-process-
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`ing enzymes. Individuals born with no meaningful residual
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`urea synthetic capacity typically present in thefirst few days
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`oflife (neonatal presentation). Individuals with residual func-
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`tion typically present later in childhoodor even in adulthood,
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`and symptomsmaybeprecipitated by increased dietary pro-
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`tein or physiological stress (e.g. intercurrent illness.) Some
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`enzymes whosedeficient functioning causes UCDsinclude
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`the following:
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`[0007] Carbamy] phosphate synthetase (CPS),
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`ornithine transcarbamylase (OTC),
`[0008]
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`argininosuccinate synthetase (ASS),
`[0009]
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`argininosuccinate lyase (ASL),
`[0010]
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`arginase (ARG; EC Number3.5.3.1; autosomal
`[0011]
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`recessive), (ARG) and
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`[0012] N-acetyl glutamine synthetase (NAGS)
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`[0013] Mitochondrial transporter deficiency states which
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`mimic many features of urea cycle enzymedeficiencies, and
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`thus emulate UCDs and are treatable by the methods
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`described herein for treating UCDs, include the following:
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`[0014] Omithine translocase deficiency (hyperorni-
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`thinemia, hyperammonemia, homocitrullinuria or HHH
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`Syndrome)
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`[0015] Citrin (aspartate glutamate transporter) defi-
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`ciency
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`[0016] The common feature of UCDs andsimilar condi-
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`tions and hepatic encephalopathy that render them treatable
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`by methods of the invention is an accumulation of excess
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`waste nitrogen in the body, and hyperammonemia. CRF is
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`similarly characterized by build-up of excessive waste nitro-
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`gen in the blood in the form urea, and the ammonia scaveng-
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`ing drugs described herein are likewise effective to prevent
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`accumulation of excess levels of urea. In normalindividuals,
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`the body’s intrinsic capacity for waste nitrogen excretion is
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`greater than the body’s waste nitrogen production, so waste
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`nitrogen does not accumulate and ammonia doesnot build up
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`to harmful levels. For patients with nitrogen retention states
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`Page 19 of 48
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`US 2012/0022157 Al
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`Jan. 26, 2012
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`such as UCD or HE,the body’s intrinsic capacity for waste
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`nitrogen excretion is less than the body’s waste nitrogen
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`production based on a normal diet that contains significant
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`amountsofprotein. As aresult, waste nitrogen builds up in the
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`body of a patient having a nitrogen retention disorder, which
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`usually results in excess ammonia in the blood. This has
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`various toxic effects; drugs that help eliminate the excess
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`ammonia are an important part of an overall management
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`strategy for such disorders.
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`To avoid build-up of ammonia to toxic levels in
`[0017]
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`patients with nitrogen retention states, dietary intake of pro-
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`tein (a primary source of exogenous waste nitrogen) must be
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`balancedby the patient’s ability to eliminate excess ammonia.
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`Dietary protein can be limited, but a healthy diet requires
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`sufficient protein to support normal growth (1.e. in growing
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`children) and repair; thus in addition to controlling dietary
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`protein intake, drugsthat assist with elimination of nitrogen
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`are used to reduce ammonia build-up (hyperammonemia).
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`The capacity to eliminate excess ammonia in treated patients
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`can be considered the sum ofthe patient’s endogenous capac-
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`ity for nitrogen elimination (if any) plus the amountof addi-
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`tional nitrogen-elimination capacity that is provided by a
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`nitrogen scavenging drug. The methodsofthe invention use a
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`variety of different drugs that reduce excess waste nitrogen
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`and ammonia by converting it to readily-excreted forms, such
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`as phenylacetyl glutamine (PAGN). In some embodiments,
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`the invention relates to methods for determining or adjusting
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`a dosage of an oral drug that forms PAA in vivo, which is
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`converted into PAGN,whichis then excreted in urine and thus
`
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`helps eliminate excess nitrogen.
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`[0018] Based on prior studies in individual UCDpatients
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`(e.g. Brusilow, Pediatric Research, vol. 29, 147-50 (1991);
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`Brusilow and Finkelstien, J Metabolism, vol. 42, 1336-39
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`(1993)) in which 80-90% of the nitrogen scavenger sodium
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`phenylbutyrate (a PAA prodrug) was reportedly excreted in
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`the urine as PAGN,current treatment guidelines typically
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`either assume complete conversion of sodium phenylbutyrate
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`or other PAA prodrugs to PAGN (e.g. Berry et al., J. Pediat-
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`rics, vol. 138, S56-S61 (2001)) or do not comment on the
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`implications of incomplete conversion for dosing (e.g. Singh,
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`Urea Cycle Disorders Conference Group ‘Consensus State-
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`mentfrom a Conferencefor the Management ofPatients with
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`Urea Cycle Disorders’, Suppl to J Pediatrics, vol. 138(1),
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`$1-S5 (2001)). Based on what is known, one expects essen-
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`tially complete conversion of these drugs into urinary PAGN.
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`[0019]
`PBA is currently the preferred nitrogen scavenging
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`drug for UCDpatients in need of substantial nitrogen elimi-
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`nation capacity. Current treatment guidelines recommend 4
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`timesper day dosing with PBA,based on the fact that PBA is
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`absorbed rapidly from the intestine when administered in the
`form of sodium PBA and exhibits a short half life in the
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`bloodstream (Urea Cycle Disorders Conference Group ‘Con-
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`sensus Statement’ 2001). Current
`recommendations for
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`sodium phenylbutyrate dosing in UCDpatients indicate that
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`dosage should not exceed 600 mg/kg (for patients weighing
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`up to 20 kg) or in any case 20 gramstotal per day. Frequent
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`dosing helps minimize the peak levels of ammonia, which can
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`be very harmful, and it minimizes buildup of high concentra-
`tions of PAA as well.
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`[0020] CRF (chronicrenal failure) resulting from a variety
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`of causes (e.g. diabetes, hypertension, glomerular disease,
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`etc.) is associated with diminished excretion from the body of
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`water soluble waste products normally present in the urine,
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`including nitrogenous waste such as urea. While the contri-
`Page 20 of 48
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`bution of increased bloodlevels of urea, perse, to the clinical
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`manifestations of CRF and end-stage renal disease (ESRD)
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`known as uremia is uncertain, urea levels in the blood are
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`commonly used as one measure ofrenal function and the need
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`for and frequency ofrenal replacementtherapy suchas dialy-
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`sis. Asa corollary ofthe findings noted above in UCDpatients
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`(e.g. Brusilow, Pediatric Research, vol. 29, 147-50 (1991);
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`Brusilow and Finkelstien, Metabolism, vol. 42, 1336-39
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`(1993)), increased waste nitrogen excretion in the form of
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`PAGN resulting from administration of PAA prodrugs
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`decreases urea synthesis and therefore can serve as an alter-
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`native to urea excretion. Consistent with this, Brusilow (U.S.
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`Pat. No. 4,284,647) has demonstrated that administration of
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`sodium benzoate, which increases waste nitrogen excretion in
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`the form of hippuric acid, lowered blood urea levels in a
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`patient with renal failure (FIG. 14). Accordingly, PAA pro-
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`drugs, including PBA and HPN-100 can be usedto treat CRF
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`as well as UCDs and HE, and methods for determining and
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`adjusting dosage ofthese PAA prodrugs and monitoringtreat-
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`mentefficacy are amongthe inventions disclosed herein. In
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`general, and without being limited by theory, prodrugs of
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`PAA which do not contain sodium would be preferred for
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`treatment of treatment of those nitrogen retention states,
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`including CRFas well as cirrhosis and HE, which are also
`knownto be associated with sodium andfluid retention mani-
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`fested, for example, as ascites and or peripheral edema. HPN-
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`100 is one such sodium-free PAA prodrug.
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`DISCLOSURE OF EMBODIMENTSOF THE
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`INVENTION
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`[0021] The invention provides a novel approach for deter-
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`mining and adjusting the schedule and dose oforally admin-
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`istered nitrogen scavenging drugs, including sodium phenyl-
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`butyrate and glyceryl
`tri-[4-phenylbutyrate]
`(HPN-100),
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`based uponthe urinary excretion of the drug metabolite phe-
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`nylacetylglutamine (PAGN)and/ortotal urinary nitrogen.It
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`is based in part on the discovery that bioavailability of these
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`drugs as conventionally assessed based on systemic blood
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`levels of the drugs themselves or of the active species pro-
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`duced in vivo from these drugs does not accurately predict
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`removalofwaste nitrogen or reduction ofplasma ammonia in
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`healthy human volunteers, adults with liver disease, or
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`patients with UCDsreceiving ammonia scavenging drugs as
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`defined below. Conversion of orally administered sodium
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`phenylbutyrate (NaPBA, or sodium PBA) to urinary PAGN
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`(uPAGN)is now shownto be incomplete: conversion is typi-
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`cally about 40-70%, or about 54% on average. (A preliminary
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`analysis suggested the range would be around 60-75%, but
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`final analysis shows the average is about 54%.) The average
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`value of about 54% conversion was determined experimen-
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`tally for orally administered HPN-100 or PBA converting into
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`urinary PAGN, and a range of about 40-70% represents the
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`average plus or minus approximately one standard deviation
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`for this data set. By comparison, correlating urinary PAGN
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`with drug dosage using information available in the art would
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`have provided substantially different results, since the prior
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`art suggests a much higher conversion, e.g., 90% or more. As
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`used in this context, “about 54%”refers to a value between
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`50% and 60%, and the urinary PAGN output refers to a
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`measure of urinary PAGN output for a subject receiving
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`ongoingstable daily dosagesofthe nitrogen scavenging drug.
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`[0022] Urinary PAGN can be measured in various ways; in
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`some embodiments, as described herein,it is a 24-hour mea-
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`surement, which means measurementof total urinary PAGN
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`Page 20 of 48
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`US 2012/0022157 Al
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`Jan. 26, 2012
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`output for a period of 24 hours followingthefirst dose of the
`day of a nitrogen scavenging drug. In other embodiments, a
`12-24 hour urinary PAGN level is used, which is the total
`amountof urinary PAGN excreted overthe time period 12-24
`hours after the first dose of the day. As an alternative, as
`described herein,spot testing of urinary PAGNlevels can be
`used, by normalizing the valueas a ratio to urinary creatinine
`output. Daily creatinine outputis relatively stable for most
`subjects, and this has been foundto be true even in the UCD,
`HE, and CRF patients receiving the nitrogen scavenging
`drugs described herein. Because creatinine output is rela-
`tively stable, it can be used to normalize urinary PAGN output
`levels: from a ‘spot test’ of a partial sample, the ratio of
`uPAGNto urinary creatinine can be usedto estimate a total
`daily urinary PAGN output. These values may be used in
`calculations of dosages or protein intake based on urinary
`PAGNoutput as well as for determining initial drug dosage
`for a patient taking a given amountofprotein.
`[0023] The invention further provides methods to easily
`monitor treated patients to determine from urinary PAGN
`output whether their overall treatment program (diet and
`medication) is working, and whenthe patient needs a modi-
`fied treatment program or adjusted drug dosage. These meth-
`ods comprise monitoring urinary PAGNoutput,either as a 24
`hour output, or as a 12-24 hourtotal urinary PAGN output, or
`as an estimated value from a spot test, where the urinary
`output is normalizedto urinary creatinine and converted to an
`estimated 24-hour (or 12-24 hour) output. In one embodi-
`ment, the method comprises comparingthat value for urinary
`PAGNto a cut-off value that distinguishes patients likely to
`have normal ammonialevels from patientslikely to have high
`ammonialevels.
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`Prodrugs of phenylbutyrate (PBA,the active ingre-
`[0024]
`dient in BUPHENYL® (sodium phenylbutyrate), which is
`the sodium salt of PBA along with small amounts of inert
`ingredients), which is itself a prodrug of phenylacetic acid
`(PAA), are especially subject to the effects described herein.
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`COyNat
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`phenylbutyrate
`OH
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`0
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`Phenylacetic acid
`NH
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`0.
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`Phenylacetylglutamine
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`[0025] As used herein “ammonia scavenging drugs” is
`defined to include all orally administered drugs in the class
`which contain or are metabolized to phenylacetate. Thus, the
`Page 21 of 48
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`term includes at least phenylbutyrate, BUPHENYL® (so-
`dium phenylbutyrate), AMMONAPS®, butyroyloxymethyl-
`4-phenylbutyrate, glyceryl
`tri-[4-phenylbutyrate]
`(HPN-
`100), esters, ethers, and acceptable salts, acids and derivatives
`thereof. These drugs reduce high levels of endogenous
`ammonia by providing phenylacetic acid in vivo, which is
`metabolized efficiently to form phenylacetyl glutamine
`(PAGN). PAGNisefficiently excreted in urine, carrying away
`two equivalents of nitrogen per mole of PAA converted to
`PAGN. References herein to sodium phenylbutyrate are
`understoodto include reference to the drug product BUPHE-
`NYL®, and BUPHENYL®wasusedfor the Examples herein
`wherever test subjects were treated with sodium phenylbu-
`tyrate. Thus the sodium PBA dosages used in the Examples
`generally refer to a dosage of BUPHENYL®, and the
`amounts of sodium phenylbutyrate in those Examples should
`be interpreted accordingly. Note that the terms ‘ammonia
`scavenger’ and ‘nitrogen scavenger’ are used interchangeably
`in this invention, reflecting the fact that the drugs described
`herein lower blood ammonia and/or urea levels through
`eliminat