as) United States
`a2) Patent Application Publication (0) Pub. No.: US 2010/0008859 Al
`(43) Pub. Date:
`Jan. 14, 2010
`SCHARSCHMIDT
`
`US 20100008859A1
`
`(54) METHODS OF TREATMENTUSING
`AMMONIA-SCAVENGING DRUGS
`
`(76)
`
`Inventor:
`
`Bruce SCHARSCHMIDT, South
`
`San Francisco, CA (US)
`
`Correspondence Address:
`MORRISON & FOERSTER LLP
`12531 HIGH BLUFF DRIVE, SUITE 100
`SAN DIEGO, CA 92130-2040 (US)
`
`(21) Appl. No.:
`
`12/350,111
`
`(22)
`
`Filed:
`
`Jan. 7, 2009
`
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 61/093,234, filed on Aug.
`29, 2008, provisional application No. 61/048,830,
`filed on Apr. 29, 2008.
`
`Publication Classification
`
`(51)
`
`Int.Cl.
`(2006.01)
`AGIK 49/00
`(2006.01)
`AGIK 31/192
`(2006.01)
`AGIP 13/00
`(62) USiChicnsnanmacinasaian 424/9.2; 514/568
`
`(57)
`
`ABSTRACT
`
`The invention provides a method for determining a dose and
`schedule and making dose adjustments of PBAprodrugs used
`to treat nitrogen retention states, or ammonia accumulation
`disorders, by measuring urinary excretion of phenylacetyl-
`glutamine and/or total urinary nitrogen. The invention pro-
`vides methods to select an appropriate dosage of a PBA
`prodrug based on thepatient’s dietary proteinintake, or based
`onprevious treatments administeredtothe patient. The meth-
`ods are applicable to selecting or modifying a dosing regimen
`for a subject receiving an orally administered ammonia scav-
`enging drug.
`
`Sodium Phentybutyrate.
`
`
`
`1
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`LUPIN EX. 1007
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`Jan. 14,2010 Sheet 1 of 15
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`US 2010/0008859 Al
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`Figure 1
`
`Ketoglutarets
`
`NH’,
`
`Sodium Phentybutyrate.
`¥
`
`HC
`
`ATP
`
`3V
`
`v
`Urine excretion
`AA
`id
`i
`?
`
`|| {ii
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`Figure 2
`
`A conventionalclinical pharmacology model in which only drug reachingthe central (systemic)
`circulation is assumed to be active.
`
`PK/PD Modeling of PBA/PAA/PAGN/UPAGN
`- Conventional Approach-
`
`HPN-100 or
`Buphenyl®
`
`Note:
`
`This modelonly allows for conversion of PBA to
`PAA to PAGN in the systemic (labeled ‘central’)
`Oral|Dose
`plasma compartment. Bioavailability and drug
`effect is assumeto relate directly to plasma
`
`Fo:
`‘
`Ceueweee Bese cesar
`
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`metabolite concentations
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`ppPlasma(Centralcompartment)
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`BSA/1.73 x VM1, VM2, VPB, VPA, VPG
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`Jan. 14, 2010
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`METHODS OF TREATMENT USING
`AMMONIA-SCAVENGING DRUGS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application claims benefit of priority to U.S.
`Provisional application Ser. No. 61/093,234, filed Aug. 29,
`2008, whichis incorporated herein by reference inits 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, Ser. No. 61/048,830, filed on
`Apr. 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 elimina-
`tion of waste nitrogen fromthe body. The compounds can be
`orally administered small-molecule drugs, and the invention
`provides methodsfor delivering these compoundsandselect-
`ing 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 pro-
`drugs of phenylacetic acid (PAA), measuring the blood level
`of the prodrug (e.g. PBA) or of PAA formed fromit is unre-
`liable. In addition, assessment of treatment effect by measur-
`ing levels of ammonia in the blood is inconvenient, because it
`requires withdrawing multiple blood samples undercarefully
`controlled conditions. Because blood ammonia levels are
`affected by variousfactors including dietary protein, they also
`fail to provide a direct measure of how much ammonia the
`drug is mobilizing for elimination. The invention demon-
`strates that prodrugs 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 UCDs. It is particularly applicable to prodrugs
`that liberate or are metabolized to form phenylacetic acid, 1.¢.,
`prodrugs of PAA, and those prodrugs that are metabolized to
`form PBA.
`[0004] Hepatic encephalopathy refers to a spectrum ofneu-
`rologic signs and symptoms which frequently occur in
`patients with cirrhosis or certain other types ofliver 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
`FIG. 1, which also illustrates how certain ammonia-scaveng-
`ing drugsact to assist in elimination of excessive ammonia.
`The enzymes including their Enzyme Commission (EC)
`numbers and modesofinheritance include the following:
`[0006] Carbamyl! phosphate synthetase (CPS: EC Num-
`ber 6.3.4.16; autosomal recessive),
`[0007]
`ornithine transcarbamylase (OTC; EC Number
`2.1.3.3; X-linked),
`
`argininosuccinate synthetase (ASS; EC Number
`[0008]
`6.3.4.5; autosomal recessive),
`[0009]
`argininosuccinate lyase (ASL; EC Number4.3.2.
`1; autosomal recessive),
`[0010]
`arginase (ARG; EC Number 3.5.3.1; autosomal
`recessive), and
`[0011] N-acetyl glutamine synthetase (NAGS 1; EC
`Number2.3.1.1; autosomal recessive)
`[0012] Mitochondrial transporter deficiency states which
`mimic many features of urea cycle enzyme deficiencies
`include the following:
`[0013] Omithinetranslocase deficiency (hyperomithine-
`mia, hyperammonemia, homocitrullinuria or HHH Syn-
`drome)
`[0014] Citrin (aspartate glutamate transporter) defi-
`ciency
`[0015] The commonfeature of UCD and hepatic encepha-
`lopathy that render them treatable by methods of the inven-
`tion is an accumulation of excess waste nitrogen inthe body,
`and hyperammonemia. In normal
`individuals,
`the body’s
`intrinsic capacity for waste nitrogen excretion is greater than
`ithe body’s waste nitrogen production, so waste nitrogen does
`not accumulate and ammonia does not build up to harmful
`levels. For patients with nitrogen retention states such as
`UCD orHE, the body’sintrinsic capacity for waste nitrogen
`excretion is less than the body’s waste nitrogen production
`based on a normal diet that contains significant amounts of
`protein. As a result, nitrogen builds upin the body ofa patient
`having a nitrogen retention disorder, and usually results in
`excess ammonia in the blood. This has various toxic effects;
`drugsthat help eliminate the excess ammonia are an impor-
`tant part of an overall management strategy for such disor-
`ders.
`
`[0016] To avoid build-up of ammonia to toxic levels in
`patients with nitrogen retentionstates, dietary intake of pro-
`tein (a primary source of exogenous waste nitrogen) must be
`balanced bythepatient’s ability to eliminate excess ammonia.
`Dietary protein can be limited, but a healthy diet requires a
`significant amount ofprotein, particularly for growing chil-
`dren; thus in addition to controlling dietary protein intake,
`drugs that assist with elimination of nitrogen are used to
`reduce ammonia build-up (hyperammonemia). The capacity
`to eliminate excess ammonia in treated patients can be con-
`sidered the sum ofthe patient’s endogenous capacity for
`nitrogen elimination (if any) plus the amount of additional
`nitrogen-elimination capacity that is provided by a nitrogen
`scavenging drug. The methods of the invention use a variety
`of different drugs that reduce excess waste nitrogen and
`ammonia by converting it to readily-excreted forms, such as
`phenylacetyl glutamine (PAGN). In some embodiments, the
`invention relates to methods for determining or adjusting a
`dosage of an oral drug that forms PAA in vivo, which is
`converted into PAGN, whichis then excreted in urine and thus
`helps eliminate excess nitrogen.
`[0017] Based on prior studies in individual UCD patients
`(e.g. Brusilow, Pediatric Research, vol. 29, 147-50 (1991):
`Brusilow and Finkelstien, . Metabolism, vol. 42, 1336-39
`(1993)) in which 80-90% ofthe nitrogen scavenger sodium
`phenylbutyrate was reportedly excreted in the urine as PAGN,
`current treatment guidelines typically either assume complete
`conversion of sodium phenylbutyrate or other PAA prodrugs
`to PAGN(e.g. Berry et al., J. Pediatrics, vol. 138, 856-S61
`(2001)) or do not commentonthe implications of incomplete
`conversionfor dosing (e.g. Singh, Urea Cycle Disorders Con-
`
`17
`17
`
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`
`ference Group ‘Consensus Statement from a Conference for
`the Management of Patients with Urea Cycle Disorders’,
`Suppl to J Pediatrics, vol. 138(1), S1-S5 (2001)).
`[0018] Current treatment guidelines recommend 4 times
`per day dosing, based on thefact that PBA is absorbed rapidly
`fromthe intestine when administered in the form of sodium
`PBAandexhibits a short halflife in the bloodstream (Urea
`Cycle Disorders Conference Group “Consensus Statement’
`2001)
`[0019] Current recommendations for sodium phenylbu-
`tyrate dosing indicate that dosage should not exceed 600
`mg/kg (for patients weighing up to 20 kg) or in any case 20
`gramstotal.
`
`DISCLOSURE OF EMBODIMENTSOF THE
`INVENTION
`
`[0020] The invention provides a novel approach for deter-
`mining and adjusting the schedule and dose of orally admin-
`istered nitrogen scavenging drugs, including sodium phenyl-
`butyrate and glyceryl
`tri-[4-phenylbutyrate]
`(HPN-100),
`based uponthe urinary excretion ofthe drug metabolite phe-
`nylacetylglutamine (PAGN) and/ortotal urinary nitrogen, It
`is basedinpart on the discoveriesthat bioavailability of these
`drugs as conventionally assessed based on systemic blood
`levels of the drugs themselves or of the active species pro-
`duced in vivo from these drugs does not accurately predict
`removalof waste nitrogenor reduction ofplasma ammonia in
`healthy human volunteers, adults with liver disease, or
`patients with UCDsreceiving ammonia scavenging drugs as
`defined below and that conversion of orally administered
`sodium phenylbutyrate (NaPBA, or sodium PBA) to PAGNto
`urinary PAGN is incomplete, typically about 60-75%. Pro-
`drugs of phenylbutyrate (PBA,
`the active ingredient
`in
`BUPHENYL® (sodium phenylbutyrate), which is
`the
`sodium salt of PBA along with small amountsofinert ingre-
`dients), whichis itself'a prodrug of phenylacetic acid (PAA),
`are especially subject to the effects described herein.
`
`‘COsNat*
`
`phenylbutyrate
`OH
`
`oO
`
`Phenylacetic acid
`NH)
`
`0.
`
`oO
`
`HO
`
`oO
`
`“uy,
`
`ty NH
`
`Phenylacetylglutamine
`
`[0021] 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
`term includes at least phenylbutyrate, BUPHENYL®(so-
`dium phenylbutyrate), AMMONAPS®, butyroyloxymethyl-
`4-phenylbutyrate, glyceryl
`tn-[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, whichis
`metabolized efficiently to form phenylacety] glutamine
`(PAGN). PAGNis efficiently excreted in urine, carrying away
`two equivalents of nitrogen per mole of PAA converted to
`PAGN. References herein to sodium phenylbutyrate are
`understood to include reference to the drug product BUPHE-
`NYL®, and BUPHENYL®wasused for the Examples herein
`wherevertest 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 sodiumphenylbutyrate 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 through elimination of waste
`nitrogen in the form of PAGN.
`[0022]
`In some embodiments, the invention uses prodrugs
`that can be converted into PAA within the body. Sodium
`phenylbutyrate (sodium PBA) is one suchdrug;it is converted
`by oxidative mechanisms into PAA in the body.HPN-100 is
`anothersuchdrug:it can be hydrolyzed to release PBA, which
`in turn can be oxidized to form PAA. Thus, HPN-100 is a
`prodrug of PBA, and also a prodrug of PAA. Clinical evi-
`dence demonstrates that HPN-100 is converted into PAA in
`the body as expected, and that PAA is then linked to a mol-
`ecule of glutamine and converted into PAGN, whichis elimi-
`nated in the urine as predicted. This process can be summa-
`rized as follows:
`HPN-100—-+3PBA—*3PAA
`
`PAA+glutamine—PAGN.
`
`PAGNis mainly excreted in the subject’s urine, and
`[0023]
`removes two molecules of ammonia per molecule ofexcreted
`PAGN, Each HPN-100 molecule forms three PAA molecules,
`so each molecule of HPN-100 can promote excretionof six
`molecules of ammonia. The clinical results suggest that con-
`version of HPN-100 into PBA and PAAis efficient and fairly
`rapid, but surprisingly suggest that some conversion of HPN
`to PAGN may occur before the HPN-100 (or PBA, or PAA
`derived from PBA) enters systemic circulation. As a result,
`systemic levels of PAA or PBA are not reliably correlated
`with the efficacy of HPN-100 as an ammonia scavenger.
`[0024]
`Insome embodiments, the invention uses a prodrug
`of PBA, including HPN-100 and other esters of phenylbu-
`tyrate. The PBA prodrugis thus a prodrug ofa prodrug, since
`PBAacts to scavenge ammonia afterit is converted to PAA
`and is thus considered a prodrug of PAA. In some embodi-
`ments, the PBA prodrugis an ester of phenylbutyrate, such as
`those described below; a preferred PBA prodrugfor use in the
`invention is HPN-100. These compounds can be made and
`used by methods disclosed in U.S. Pat. No. 5,968,979, which
`is incorporated herein by reference forits description ofthese
`compounds and methods for their administration.
`[0025] Where an ‘equal molar’ or ‘equimolar’ amount of a
`second drug is to be used along with or instead of a certain
`amountofa first drug, the amount ofeachdrug is calculated
`on a molar basis, and the equimolar amount of the second
`drug is the amount that produces an equal molar amount of
`active drug in vivo. Where oneofthe drugsis a prodrug, the
`amountofprodrug will typically refer to the molar amount of
`the active species formed from that prodrug. ‘Thatactive spe-
`cies is usually PAA for the prodrugs described herein, and the
`molaramount ofa prodrug correspondsto the amount of PAA
`that would form in the body fromthat amountof the prodrug,
`assuming complete conversion into PAA occurs in vivo.
`
`18
`18
`
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`
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`

`US 2010/0008859 Al
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`Jan. 14, 2010
`
`the triol backboneliberated by hydrolysis ofthe esters is
`glycerol, a normal constituent ofdietary triglyceride
`whichis non-toxic.
`
`[0030] The present invention also utilizes phenylbutyrate
`and phenylacetate prodrugs ofthe formula II:
`
`oO
`
`r—ol Ry
`
`dp
`
`[0031] wherein R is aC,-C,, alkyl group,
`[0032]
`Ry, is
`
`(CH), S or
`(CyH2y.2) 7
`
`and nis zero or an even number, and m is an even
`
`[0033]
`number.
`In Formula II, R can be, for example, ethyl, propyl,
`[0034]
`isopropyl, n-butyl, andthe like.
`[0035] The compounds ofthe invention are esters of the
`congeners of phenylalkanoic and phenylalkenoic acids hav-
`ing an even number of carbon atoms in the alkanoic acid
`portion, whichinclude phenylacetic acid esters and those of
`phenylbutyric acid, etc., which can be converted by efficient
`beta-oxidation processes to phenylacetic acid in the body.
`They are thus prodrugs for phenylacetic acid. Where n is 2 or
`4, the esters are also prodrugs for phenylbutyric acid. Prefer-
`ably the alkylene or alkenylene carboxylate group contains 24
`or fewer carbon atoms, so n or mis less than 24. In some
`embodiments, n and m are 0, 2, 4 or 6, and in somepreferred
`embodiments n or mis 2.
`
`[0036] Certain preferred embodimentsofthe invention use
`HPN-100 (Formula II):
`
`(I)
`
`oO
`
`oO
`
`oO
`
`oO
`
`H
`
`H
`
`H
`
`H H
`
`‘Total daily dosage ofprodrugslike sodium PBA can
`[0037]
`often be selected according to the amount needed to provide
`
`19
`19
`
`19 of 39
`
`Thus, for example, a molecule of HPN-100 can be metabo-
`lized by ester hydrolysis followed by oxidation to form three
`molecules of PAA, so a mole of HPN-100 would be consid-
`ered equimolar to three moles of PAA. Similarly, since HPN-
`100 hydrolyzes to form three molecules of PBA (and one
`molecule of glycerin), an equimolar amount of HPN-100
`would be one-third of the molar amount of PBA.
`
`[0026] The following Table sets forth amounts of HPN-100
`that correspond to equimolar amounts of certain relevant
`doses of BUPHENYL®(sodium phenylbutyrate). Note that
`the conversion of the dose of sodium PBA to the dose of
`HPN-100 involves correction for their different chemical
`forms[i.e. HPN-100 consists of glycerolin ester linkage with
`3 molecules of PBA and contains no sodium; (sodium PBA
`[g]x0.95=HPN-100 [g])] as well as correction for the specific
`gravity of HPN-100, whichis 1.1 g/mL.
`
`BUPHENYL ®
`(sodium PBA)
`
`450-600 meg/ke/day
`(patients = 20 kg)
`9.9-13.0 g/m2/day
`(patients > 20 kg)
`MaximumDaily
`Dose: 20 2
`
`HPN-100 PBA
`Equivalent
`Dose (mg)
`
`HPN-100 PBA
`Equivalent
`Dose (mL)
`
`428-570 mg/kg/day
`
` 0.39-0.52 mL/ke/day
`
`9.4-12.4 g/m2/day
`
`8.6-11.2 mL/m2/day
`
`Maximum Daily
`Dose: 19 g
`
`17.4 mL
`
`[0027] The present invention can use prodrugs of the for-
`mula (1):
`
`(D)
`
`H
`
`H
`
`H
`
`H
`
`H
`
`O—R,
`
`O—R;
`
`O—R;
`
`[0028] wherein R,, R,, and R, are independently, H,
`
`.H)a
`
`CyX)‘Qn3
`
`and nis zero or an even number, m is an even
`[0029]
`numberandat least one of R,. R5, and R, is not H. For
`each R,, R5, or Ry, n or m is independently selected, so
`the R,. R,, and R, groups ina compound of formula | do
`not have to be identical. The preferred compounds are
`those wherein none of R,, R;, and R, is H, and fre-
`quently each n or mfor a particular embodimentis the
`same, i.e., R,, R,, and R, are all the same. The advantage
`over the prior art of decreased dosage is greater with
`such triesters, and havingall three acyl groups the same
`reducesissues related to mixtures of isomers. Moreover,
`
`19 of 39
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`

`US 2010/0008859 Al
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`
`an appropriate amountofthe active species, if that amountis
`known or can be determined. PBA is a prodrug for PAA:
`therefore, an initial dose of PBA could be selected if an
`effective dosage of PAA were known, takinginto accountthe
`fraction of PBAthat is converted into PAA and ultimately into
`PAGN. Ifa subject has been treated with PAA or a prodrug
`that forms PAAin the body, the amountofthe previously used
`drug that was effective provides a possible starting pointfor
`selecting a dosage of a new prodrug of PAA. In this same
`patient, after the new prodrug is administered at the expected
`PAA dose equivalence, the PAA levels in the subject could be
`monitored andthe dose of the prodrug adjusteduntil the same
`plasma level of PAA that was effective with the previous
`treatmentis achieved. However, the current invention is based
`in part on finding that plasma PAA and PBAlevels are not
`well correlated with the dose ofa PBA prodrug administered
`or with ammoniaelimination; for monitoring a dosing level of
`a PBAprodrug, one should not rely upon these parametersto
`assess the effectiveness of the prodrug. While not bound by
`the underlying theory, explanations for this effect (i.e. the
`inconsistent relationship between ammonia scavenging and
`PBAand/or PAA bloodlevels) are provided herein.
`[0038] The following Table provides data from three clini-
`cal test groups showing the inconsistent relationship between
`plasma PAA and PBA levels among healthy volunteers,
`patients with cirrhosis and UCD patients, despite that fact
`that, as described indetail below, all groups exhibited similar
`ammonia scavenging activity based on urinary excretion of
`PAGN. Overall, this shows that urinary PAGN provides a
`convenient method for monitoring ammonia elimination
`induced by the administered drug, which does not require
`drawing blood and directly relates to the actual nitrogen
`elimination provided by the administered nitrogen scaveng-
`ing drug without being influenced by the many other factors
`that can affect plasma ammonia levels.
`
`Plasma Pharmacokinetics of PBA, PAA, and PAGN Comparison across
`Studies
`
`Analyte
`
`Treatment
`
`Ce
`(ug/mL)
`
`Tox
`(h)
`
`TY
`(h)
`
`AUC34
`(ug + mL)
`
`PAA
`
`Healthy Volunteers (Single Dose - 3 g/m?/day PBA Mole Equivalent)
`PBA
`Sodium PBA
`221.0
`0,9
`0,7
`542.6
`HPN-100
`37.0
`2.4
`19
`137.2
`Sodium PBA
`58.8
`3.9
`1.2
`279.8
`HPN-100
`14.9
`4.0
`NC
`70.9
`Sodium PBA
`63.1
`aoe
`1.7
`395.1
`HPN- 100
`30.2
`4.0
`NC
`262.1
`Healthy Volunteers and Cirrhotic Patients (100 mg/kg BID)!
`
`PAGN
`
`PBA
`
`PAA
`
`PAGN
`
`1.2
`2.3
`42.8
`Child-Pugh A
`34
`2.9
`41.8
`Child-Pugh B
`19
`3.1
`44.3
`Child-Pugh C
`2.1
`3.0
`29.8
`Volunteers
`18
`3.8
`33.2
`Child-Pugh A
`2.8
`4,5
`30.8
`Child-Pugh B
`Ty
`48
`53.1
`Child-Pugh C
`19
`3.6
`25.5
`Volunteers
`5.0
`3.9
`37.7
`Child-Pugh A
`75
`4.0
`38.1
`Child-Pugh B
`4.0
`5.3
`43.1
`Child-Pugh C
`V2
`4.3
`46,3
`Volunteers
`UCD Subjects (Multiple Dose - PBA Mole Equivalent)
`
`131.7
`189.5
`192.1
`132.7
`168.8
`252.4
`579.9
`130.5
`335.1
`466.99
`578.4
`5509
`
`PBA
`
`Sodium PBA
`HPN-100
`
`141.0
`70.1
`
`2.1
`6.1
`
`NC
`NC
`
`739.0
`340.0
`
`-continued
`
`Plasma Pharmacokinetics of PBA, PAA, and PAGN Comparison across
`Studies
`
`Analyte
`PAA
`
`PAGN
`
`Treatment
`Sodium PBA
`HPN-100
`Sodium PBA
`HPN-LOO
`
`Cas
`(ue/mL)
`53.0
`40.5
`83.3
`ng
`
`Tiare
`(h)
`8.1
`8.0
`7.2
`8.0
`
`TA
`(h)
`NC
`NC
`3.9
`48
`
`AUC34
`(ug + vmL)
`595.6
`574.6
`1133.0
`1098.0
`
`Cnax = Maximum plasma concentration;
`Trax = time of maximum plasma concentration:
`AUC3, =AUCfromtime 0 to 24 hours;
`NC = not calculated
`'Study did not include a sodium phenylbutyrate comparator arm, values rep-
`resent HPN-1O0 dosing only.AUC values represent the AUC fromtime 0 to
`the last measurable plasina concentration.
`
`[0039] One embodiment of the invention is a method for
`determining and/or adjusting the dose of ammonia scaveng-
`ing drugs in patients with UCDs, whereby dose would be
`based on the amountofdietary protein the patient is consum-
`ing, the anticipated percentage conversion ofthe drug to
`PAGN,andthe patient’s residual urea synthetic capacity, if
`any. Dose adjustments, if necessary, would be based on the
`observed urinary excretion of PAGN and/or total urinary
`nitrogen (TUN),the difference betweenthe tworeflecting the
`patient’s endogenous capacity for waste nitrogen excretion.
`This endogenous capacity may be absent in certain patients
`having innate urea cycle disorders due to inborn metabolic
`deficiencies, but patients with later-onset nitrogen accumula-
`tion disorders generally have some endogenous capacity,
`referred to sometimesas their residual urea synthesis capac-
`ity. See Brusilow, PROGRESS IN LIVER DISEASES, Ch. 12, pp.
`293-309 (1995). The subject’s plasma ammonia level may
`also be determined: this is a critical parameter for tracking
`effectiveness of an overall treatment program, but reflects a
`variety offactors such as dietary protein and physiological
`stress, as well as the effect ofa drug used to promotenitrogen
`excretion.
`
`[0040] Once the patient’s residual endogenous capacity for
`waste nitrogen excretion has been determined, either as the
`difference between PAGNoutputandtotal nitrogen output or
`as total urinary nitrogen output in the absence ofan ammonia
`scavenging drug, the tolerable amountofdietary protein can
`be calculated for that patient according to the dosage ofthe
`ammonia scavenging drug being administered,or the dosage
`ofthe ammonia scavenging drug can be adjusted orcalculated
`to compensate for an estimated protein intake.
`[0041] Another embodiment is a method for determining
`and adjusting the dose of an ammonia scavenging drug to be
`administered to a patient withliverdisease, including hepatic
`encephalopathy, whereby the starting dose would be based on
`the amount of dietary protein the patient is consuming, the
`anticipated conversion ofthe drug to PAGN,andthepatient’s
`residual urea synthetic capacity, if any. While the urea syn-
`thetic capacity in patients with liver disease would generally
`be greater than for patients with UCDs, considerable patient
`to patient variability would be expected among both groups
`depending, respectively, on the severity oftheir liver disease
`and the severity of their inherited enzymatic defect. Dose
`adjustments based on the observed urinary excretion of
`PAGNandtotal waste nitrogen would adjust for these indi-
`vidual patient characteristics.
`20
`20
`
`20 of 39
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`

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`
`[0042] Another embodimentis a method for determining or
`adjusting allowable dietary proteininthe diet ofa patient with
`UCD or with hepatic encephalopathy, who is being treated
`with an oral PAA-forming ammonia scavenging drug,
`whereby the amount of allowable protein would be deter-
`mined by the amount of PAGN andtotal nitrogeninthe urine.
`The difference betweentotal waste nitrogen in the urine and
`the amount of PAGN excreted is indicative of the patient’s
`endogenous waste nitrogen processing capacity. Once the
`patient’s endogenous nitrogen processing capacity is known,
`the patient’s endogenous nitrogenprocessing capacity can be
`used to adjust dietary protein intake while administering a
`fixed dosage ofan ammonia scavenging drug,or the dosage of
`the ammonia scavenging drug canbe determined accordingto
`the amount needed to facilitate elimination ofthe waste nitro-
`gen fromthe patient’s dietary protein. Dietary protein intake
`should be determined or adjusted according to how much
`nitrogen the subject can eliminate above the amount that is
`eliminated as PAGN, whichresults from the PAA-forming
`ammonia scavenging drug being administered. When making
`these calculations or adjustments, it is suitable to assumethat
`about 47% ofnitrogen inprotein will become waste nitrogen
`that needs to be excreted in the urine (the amount may be less
`for growing patients, whoretain a greater fraction ofingested
`nitrogen to support body growth), and that about 16% of
`protein, on average,is nitrogen (see Brusilow 1991).
`[0043]
`It has generally been assum