Application Data Sheet
`
`Application Information
`
`Application Type::
`
`Subject lvlatter:
`
`Regular
`
`Utility
`
`Suggested Group Art Unit::
`
`Not Yet Assigned
`
`CD-ROM or CD-R‘?::
`
`Sequence submission?:
`
`Computer Readable Form (CRF)?::
`
`None
`
`None
`
`No
`
`Tit|e::
`
`METHODS OF TREATMENT USING
`
`AMMONIA-SCAVENGING DRUGS
`
`Attorney Docket Number::
`
`643982000100
`
`Request for Early Publication’?:
`
`Request for Non-Pub|ication?::
`
`Total Drawing Sheets::
`
`Small Entity?::
`
`Petition inc|uded?::
`
`Secrecy Order in Parent Appl_’?::
`
`Applicant Information
`
`Applicant Authority Type:
`
`Primary Citizenship Country::
`
`Status::
`
`Given Name::
`
`Family Name::
`
`City of Residence:
`
`State or Province of Residence::
`
`Country of Residence:
`
`No
`
`No
`
`1 5
`
`Yes
`
`No
`
`No
`
`Inventor
`
`US
`
`Full Capacity
`
`Bruce
`
`SCHARSCHMIDT
`
`South San Francisco
`
`CA
`
`US
`
`Street of mailing address:
`
`601 Gateway Blvd. Ste. 200
`
`Sd-456535
`
`Page # 1
`
`1
`
`Initial 01r’07.n'O9
`
`LUPIN
`
`EX. 1021 (Part 1 of 6)
`
` LUPIN
`EX. 1021
`(Part 1 of 6)
`
`

`
`City of mailing address::
`
`South San Francisco
`
`State or Province of mailing address::
`
`CA
`
`Postal or Zip Code of mailing address::
`
`94080
`
`Correspondence Information
`
`Correspondence Customer Number:
`
`25225
`
`Representative Information
`
`Representative Customer Number:
`
`25225
`
`Domestic Priority Information
`
`This Application
`
`Continuit T e::
`An application
`claiming the benefit
`
`under 35 USC
`
`ParentAIication:
`61/093,234
`
`Parent Filin Date::
`08/29/08
`
`Foreign Priority Information
`
`Assignee Information
`
`Sd-456535
`
`Page # 2
`
`|nitia|01f07f09
`
`2
`
`

`
`Patent Docket: 643982000100
`
`Claims
`
`1.
`
`A method to determine an effective dosage of HPN—100 for a patient in need
`
`of treatment for a nitrogen retention disorder, which comprises monitoring the effect
`
`of an initial dosage of HPN-100,
`
`wherein monitoring the effect consists essentially of determining the
`
`patient’s urinary phenylacetyl glutamine (PAGN) output;
`
`and determining from the urinary PAGN output whether andfor how to
`
`adjust the initial dosage of HPN—100 to produce a desired ammonia scavenging
`
`effect.
`
`2.
`
`The method of claim I, wherein urinary PAGN output is determined as a
`
`ratio of the concentration of urinary PAGN to urinary creatinine.
`
`3.
`
`The method of claim 1, wherein the nitrogen retention disorder is chronic
`
`hepatic encephalopathy or a urea cycle disorder.
`
`4.
`
`The method of claim 1, wherein administering the effective dosage of HPN-
`
`100 to the patient produces a normal plasma ammonia level in the patient.
`
`5.
`
`A method to detennine an effective dosage of HPN— 100 for a patient in need
`
`of treatment for a nitrogen retention disorder, which comprises monitoring the effect
`
`of an initial dosage of HPN-100,
`
`wherein monitoring the effect consists of determining the patient’s urinary
`
`phenylacetyl glutamine (PAGN) output andfor total urinary nitrogen.
`
`6.
`
`A method to determine a dosage of HPN-100 for a patient having a nitrogen
`
`retention disorder, which comprises calculating the dosage of HPN-100 based on a
`
`utilization efficiency for HPN—100 conversion into PAGN of about 60% to about
`
`75%.
`
`7.
`
`The method of claim 6, wherein the dosage of HPN—100 is calculated from
`
`the patient‘s dietary protein intake.
`
`sd—4565'_’5
`
`55
`
`3
`
`

`
`Patent Docket: 643982000100
`
`8.
`
`The method of claim 7, wherein the dosage of HPN-100 is reduced to
`
`account for the patient’s residual urea synthesis capacity.
`
`9.
`
`A method to determine a dosage of a PAA prodru g for a patient having an
`
`ammonia retention disorder, comprising:
`
`a)
`
`b)
`
`c)
`
`cl)
`
`determining the patient’s residual urea synthesis capacity;
`
`determining the patient’s dietary protein intake;
`
`estimating from a) and b) the patient’s target urinary PAGN output;
`
`determining an amount of the PAA prodru g needed to produce the
`
`target amount of urinary PAGN,
`
`wherein about 60% to about 75% of the PAA prodmg is converted into
`
`urinary PAGN.
`
`10.
`
`The method of claim 9, wherein the PAA prodrug is phenylbutyric acid
`
`(PB A) or a pharmaceutically acceptable salt thereof.
`
`1 1.
`
`The method of claim 9, wherein the PAA prodrug is HPN-100.
`
`12.
`
`A method to treat a patient having an ammonia retention disorder with a
`
`Suitable dosage of a PAA prodrug, comprising:
`
`a)
`
`b)
`
`c)
`
`cl)
`
`determining the patient’s residual urea synthesis capacity;
`
`determining the patient‘s dietary protein intake;
`
`estimating froI11 a) and b) the patient’s target urinary PAGN output;
`
`determining an amount of the PAA prodru g needed to mobilize the
`
`target amount of urinary PAGN based on about 60% to about 75% conversion of the
`
`PAA prodrug into urinary PAGN; and
`
`e)
`
`administering to the patient the suitable dosage of the PAA prodrug.
`
`13.
`
`The method of claim 12, wherein the PAA prodrug is phenylbutyrate or a
`
`phamiaceutically acceptable salt thereof, or HPN-100.
`
`5d—4565'_’5
`
`56
`
`4
`
`

`
`Patent Docket: 643982000100
`
`14.
`
`The method of claim 12, wherein the PAA prodrug is HPN—100, the patient
`
`is a patient with clinically significant residual urea synthetic capacity, and the HPN-
`
`l00 is administered in two or three doses per day.
`
`15.
`
`A method to transition a patient receiving treatment with an initial amount of
`
`phenylacetate or phenylbutyrate to a final amount of HPN- 100, comprising:
`
`detemiining a replacement amount of HPN-100 to replace at least a portion
`
`of the phenylacetate or phenylbutyrate;
`
`substituting the replacement amount of the HPN—100 for the phenylacetate
`
`or phenylbutyrate; and
`
`monitoring the amount of urinary PAGN excreted by the patient to assess
`
`the effectiveness of the replacement amount of the HPN-100.
`
`16.
`
`The method of claim 15, wherein an increase in the amount of urinary
`
`PAGN caused by the transition indicates that the amount of HPN-100 can be
`
`reduced.
`
`17.
`
`A method to transition a patient taking an initial daily dosage of
`
`phenylbutyrate from phenylbutyrate to HPN—100, comprising
`
`a)
`
`determining a suitable amount of HPN- 100 to replace at least a
`
`portion of the initial daily dosage of phenylbutyrate;
`
`b)
`
`administering the suitable amount of HPN- 100 to the subject along
`
`with an amount of phenylbutyrate corresponding to the initial daily dosage of
`
`phenylbutyrate minus an amount corresponding to the portion replaced by HPN-
`
`100;
`
`c)
`
`d)
`
`HPN-100.
`
`determining the level of excreted urinary PAGN for the subject; and
`
`repeating steps a—c until all of the phenylbutyrate is replaced by
`
`18.
`
`A method to initiate treatment with phenylacetate, phenylbutyrate or a HPN-
`
`100 in a step-wise fashion, comprising:
`
`5d—4565'_’5
`
`57
`
`5
`
`

`
`Patent Docket: 643982000100
`
`a)
`
`estimating or measuring dietary nitrogen intake for the patient;
`
`andfor
`
`b}
`
`estimating the patient’s need for urinary waste nitrogen excretion
`
`based upon diet and urea synthetic capacity; then
`
`c)
`
`administering a starting dose of the drug estimated to provide a
`
`fraction of the necessary waste nitrogen clearance as urinary PAGN taking into
`
`account an estimated 60% to 75% conversion of the administered drug into PAGN;
`
`and
`
`d) increasing the dose of drug as appropriate, and repeating the steps above,
`
`to reach a maintenance dose of the drug.
`
`19.
`
`A method to treat a UCD patient with a PBA prodrug, wherein the prodrug
`
`produces equivalent or better ammonia level control compared to PBA without
`
`increasing the patient’s exposure to PBA as judged by the AUC and Cmax for PBA
`
`when the patient receives the PBA prodrug, when compared to the AUC and Cmax
`
`observed when the patient receives an equimolar amount of PBA.
`
`20.
`
`The method of claim 19. wherein the PBA prodrug is HPN-100.
`
`21.
`
`The method of claim 20, wherein the AUC for PBA exposure is lower with
`
`the prodrug than with PBA by at least about 20%.
`
`22.
`
`The method of claim 20, wherein the exposure to PBA upon treatment with
`
`the prodrug is lower by at least about 30% compared to treatment with PBA.
`
`23.
`
`A method to determine a suitable dietary protein level for a patient having a
`
`nitrogen retention disorder, comprising:
`
`determining the patient’s endogenous nitrogen elimination capacity;
`
`calculating from the endogenous nitrogen elimination capacity an amount of
`
`dietary protein the patient can process without the aid of a nitrogen
`
`scavenging drug;
`
`5d--’-I-565'_’5
`
`58
`
`6
`
`

`
`Patent Docket: 643982000100
`
`then adding an amount of protein that the patient should be able to process
`
`with the assistance of selected dosage of a nitrogen scavenging drug to
`
`arrive at an amount of dietary protein the patient can have while being
`
`treated with the selected dosage of the nitrogen scavenging drug, taking into
`
`account the of protein required for health and body growth.
`
`24.
`
`The method of claim 23, wherein the nitrogen scavenging drug is HPN-100.
`
`25.
`
`The method of claim 24, wherein the selected dosage of HPN— 100 is up to
`
`about 19 grams per day, and wherein the amount of dietary protein the patient
`
`should be able to process with the assistance of this amount of HPN— 100 is about 1
`
`g of protein per gram of HPN-100.
`
`26.
`
`A method to treat a patient with a PBA prodrug, comprising administering
`
`HPN-100 at a daily dose in excess of 19 g per day to a subject having HE or UCD.
`
`27.
`
`The method of claim 26, wherein the daily dose of HPN— 100 is between
`
`about 19g and about 57 g.
`
`28.
`
`A method to treat a patient having a nitrogen retention disorder with the
`
`PBA prodrug HPN-100, wherein the AUC for PBA is less than about 600 and the
`
`Cmax for PBA is less than about 100 when the PBA prodrug is administered.
`
`29.
`
`The method of claim 28, wherein the subject's plasma ammonia levels are
`
`on average normal when treated with HPN-100.
`
`sd—4565'_’5
`
`59
`
`7
`
`

`
`Patent Docket: 643982000100
`
`Abstract of the Disclosure
`
`The invention provides a method for determining a dose and schedule and making dose
`
`adjustments of PBA prodrugs used to treat nitrogen retention states, or ammonia accumulation
`
`disorders, by measuring urinary excretion of phenylacetylglutamine andfor total urinary nitrogen.
`
`The invention provides methods to select an appropriate dosage of a PBA prodrug based on the
`
`patient‘s dietary protein intake, or based on previous treatments administered to the patient. The
`
`methods are applicable to selecting or modifying a dosing regimen for a subject receiving an orally
`
`administered ammonia scavenging drug.
`
`5d—456525
`
`60
`
`8
`
`

`
`App No; Not Yet Assigned
`Inventor: Bmce SCHARSCHMIIJT
`Tide: METHODS OF TREATMENT USING AMMONIA-SCAVENGING
`DRUGS
`
`Docket No.-. 643932000100
`
`Figure 1
`
`Sodium Phen{ybi.|tyrate-
`
`sd-456525
`
`9
`
`

`
`App No.: Not Yet Assigned
`Inventor: Bruce SCHARSCHMIDT
`Tillc: METHODS OF TREATMENT USING AMMONIA-SCAVENGING
`DRUGS
`
`Docket No.: 643982-SOOIOO
`
`Figure 2
`
`A conventional clinical pharmacology model in which only drug reaching the central (systemic)
`
`circulation is assumed to be active.
`
`
`
`PK/PD Modeling of PBA/PAA/PAGN/UPAGN
`- Conventional App__roach -
`
`This model only allows for conversion of PBA to
`PM to PAGN in the systemic (labeled ‘cenlraI’)
`plasma compartment. Bioavailability and drug
`
`effect is assume to relate directly to plasma
`metabolite concentations
`
` Note:
`
`Background
`PAGN (PGBL)
`
`
`
`
`RIB. exponential
`
`
`
`Covaflate
`
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`

`
`Electronic Acknowledgement Receipt
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`Application Number:
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`12350111
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`International Application Number:
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`Confirmation N um ber:
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`Title of Invention:
`
`METHODS OF TREATMENT USING AMMONIA-SCAVENGING DRUGS
`
`First Named Inventor.-"Applicant Name:
`
`Bruce SCHARSCHNIIDT
`
`Customer Number:
`
`25225
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`Filer:
`
`Michael Glenn Smith/Jessica Conen
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`643982000100
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`07—JAN—2009
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`Application Number:
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`Title of Invention:
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`METHODS OF TREATMENT USING AMMONIA-SCAVENGING DRUGS
`
`First Named lnventormpplicant Name:
`
`Bruce SCHARSCHMIDT
`
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`
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`tarcFR1.161oI.tpi.or1uI)
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`OTHER THAN
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`on
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`

`
`DocCode — SCORE
`
`SCORE Placeholder Sheet for IFW Content
`
`Application Number: 12350111
`
`“Document Date: 1/7/2009.
`
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`Form Revision Date: October 12, 2006
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`30
`
`30
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`

`
`Patent Docket: 643982000100
`
`METHODS OF TREATMENT USING AMMONIA-SCAVENGING DRUGS
`
`Cross-Reference to Related Applications
`
`[0001] This application claims benefit of priority to U.S. Provisional application serial number
`
`6lf093,234, filed August 29, 2008, which is incorporated herein by reference in its entirety. This
`
`application is also related to the U.S. provisional patent application entitled “Treating special
`
`populations having liver disease with nitrogen-scavenging compounds," naming Sharron Gargosky
`
`as inventor, serial number 61!04-8,830, filed on April 29, 2008.
`
`Technical Field
`
`[0002] This invention relates to treatment of patients with nitrogen retention states, in
`
`particular urea cycle disorders (UCDS) and cirrhosis complicated by hepatic encephalopathy (HE),
`
`using administered compounds that assist in elimination of waste nitrogen from the body. The
`
`compounds can be orally administered small-molecule drugs, and the invention provides methods
`
`for delivering these compounds and selecting suitable dosages for a patient.
`
`Background Art
`
`[0003] Drug dosing is usually based upon measurement of blood levels of the active drug
`
`species in conjunction with clinical assessment of treatment response. However, the present
`
`invention is based on evidence that for certain prodrugs of phenylacetic acid (PAA), measuring the
`
`blood level of the prodrug (e.g. PBA) or of PAA formed from it is unreliable. In addition,
`
`assessment of treatment effect by measuring levels of ammonia in the blood is inconvenient,
`
`because it requires withdrawing multiple blood samples under carefully controlled conditions.
`
`Because blood ammonia levels are affected by various factors including dietary protein, they also
`
`fail to provide a direct measure of how much ammonia the drug is mobilizing for elimination. The
`
`invention demonstrates that prodru gs of phenylbutyric acid (PBA) behave similarly to sodium
`
`PBA, in that measuring PBA levels is unreliable for assessing their effectiveness. This invention
`
`provides a novel method for dosing in patients with nitrogen retention states, in particular patients
`
`with liver disease and clinical manifestations of hepatic encephalopathy and patients with UC Ds.
`
`It is particularly applicable to prodrugs that liberate or are metabolized to foml phenylacetic acid,
`
`i.e., prodrugs of PAA, and those prodrugs that are metabolized to form PBA.
`
`sd—4565'_’5
`
`1
`
`31
`
`31
`
`

`
`Patent Docket: 643982000100
`
`[0004] Hepatic encephalopathy refers to a spectrum of neurologic signs and symptoms which
`
`frequently occur in patients with cirrhosis or certain other types of liver disease.
`
`[0005] Urea cycle disorders comprise several inherited deficiencies of enzymes or transporters
`
`necessary for the synthesis of urea from ammonia. The urea cycle is depicted in Figure 1, which
`
`also illustrates how certain ammonia-scavenging drugs act to assist in elimination of excessive
`
`ammonia. The enzymes including their Enzyme Commission (EC) numbers and modes of
`
`inheritance include the following:
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`Carba111yl phosphate synthetase (CPS; EC Number 6.3.4.16; autosomal recessive),
`
`ornithine transcarbamylase (OTC; EC Number 2.1.3.3; X—linked),
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`argininosuccinate synthetase (ASS; EC Number 6.3.4.5; autosomal recessive),
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`argininosuccinate lyase (ASL; EC Number 4.3.2.1; autosomal recessive),
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`arginase (ARG; EC Number 3.5.3.1; autosomal recessive), and
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`N—acetyl glutamine synthetase (NAGS 1; EC Number 2.3.1.1; autosomal recessive)
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`[0006] Mitochondrial transporter deficiency states which mimic many features of urea cycle
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`enzyme deficiencies include the following:
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`I Ornithine translocase deficiency (hyperornithinemia, hyperammonemia, homocitrullinuria
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`or HHH Syndrome)
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`I Citrin (aspartate glutamate transporter) deficiency
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`[0007] The common feature of UCD and hepatic encephalopathy that render them treatable by
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`methods of the invention is an accumulation of excess waste nitrogen in the body, and
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`hyperammonemia. In normal individuals, the body’s intrinsic capacity for waste nitrogen
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`excretion is greater than the body's waste nitrogen production, so waste nitrogen does not
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`accumulate and ammonia does not build up to harmful levels. For patients with nitrogen retention
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`states such as UCD or HE, the body’s intrinsic capacity for waste nitrogen excretion is less than the
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`body’s waste nitrogen production based on a normal diet that contains significant amounts of
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`protein. As a result, nitrogen builds up in the body of a patient having a nitrogen retention
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`disorder, and usually results in excess ammonia in the blood. This has various toxic effects; drugs
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`that help eliminate the excess ammonia are an important part of an overall management strategy
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`for such disorders.
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`[0008] To avoid build-up of ammonia to toxic levels in patients with nitrogen retention states,
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`dietary intake of protein (a primary source of exogenous waste nitrogen) must be balanced by the
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`sd—4565'_’5
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`2
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`32
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`32
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`Patent Docket: 643982000100
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`patient’s ability to eliminate excess am111onia. Dietary protein can be limited, but a healthy diet
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`requires a significant amount of protein, particularly for growing children; thus in addition to
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`controlling dietary protein intake, drugs that assist with elimination of nitrogen are used to reduce
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`ammonia build—up (hyperammonemia). The capacity to eliminate excess ammonia in treated
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`patients can be considered the sum of the patient‘s endogenous capacity for nitrogen elimination (if
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`any) plus the amount of additional nitrogen—elimination capacity that is provided by a nitrogen
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`scavenging drug. The methods of the invention use a variety of different drugs that reduce excess
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`waste nitrogen and ammonia by convening it to readily—excreted forI11s, such as phenylacetyl
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`glutamine (PAGN). In some embodiments, the invention relates to methods for determining or
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`adjusting a dosage of an oral drug that forms PAA in viva, which is converted into PAGN, which is
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`then excreted in urine