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`US 20] 000U8859A1
`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2010/0008359 A1
`SCHARSCHMIDT
`(43) Pub. Date:
`Jan. 14, 2010
`
`(54)
`
`(76)
`
`.\/IETI-IODS OF TREA'l‘MEN'l‘ USING
`AMMON IA-S(.'AVE.\'GING DRUGS
`
`Inventor:
`
`Bruce SCI].-\RS(ilINIII)'I‘. Suuili
`
`Sam I’I'“.:1l1CiSCO. (‘A (US)
`
`Correspondcticc Address:
`_\/IORRISON & F()ERS'I'l£R LLI’
`12531 HIGH BLUFF DRIVE, SUITE 100
`SAN DIICGO, (TA 92130-2048 (US)
`
`(21)
`
`Appl. No;
`
`l2i'35U._ll1
`
`(22)
`
`Filed:
`
`Jan. 7. 2009
`
`Related U.S. Application Data
`
`(50)
`
`Provisional application No. 6li'0!}3.234. filed on Aitg.
`29. 2008. provisional application No. 6li’0-‘-18.830.
`filed on Apr. 29. 2008.
`
`Publication Classification
`
`(51)
`
`Int.(.'.l.
`(2006.01)
`/161K 49/00
`(2006.01)
`A6IK 31xr92
`(2()()6.0l)
`A61!’ 13/rm
`(52) U.S.(.'l. ........................................ .. 424l‘9.2;514i'568
`
`(57)
`
`.»\BS'l‘RA(?T
`
`The inveiilinn provides a method 1111' delenniniiig :1 dose and
`schedule and making dose adjustments ot'l"BA prodrugs used
`to treat nitrogen retention states. or aumionia accumulation
`disorders. by nleelstlring urinary excretion ol‘ pl1e11ylz|ce1yl-
`glulelmine emdfor lolzll ttrinelry nitmgeil. The iiwemioii pm-
`vides methods to select an appropriate dosage 0|‘ :1 PBA
`prodmg based on the patieI1I‘.~; dietary protein intake. or based
`on previous treatulenls administered In lhe pal ienl. The meth-
`ods are applicable to selecting or modifying a dosing regimen
`liar a subject receiving an orally administered ainmmtia scav-
`enging drug.
`
`Sodium Phenfy'butyrate-
`';
`I
`
`1
`
`LUPIN EX. 1007
`
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`PatentApplication Publication
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`Jan. 14, 2010 Sheet 1 of 15
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`US 2010;'0008859 A1
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`Figure 1
`
`Sodium PhenlybUtyrate-
`
`2
`2
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`PatentApplication Publication
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`US 2010;'0008859 A1
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`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 Approach -
`
`HPN-100 or
`B‘-‘P“°“Y'°
`
`_................ ..|
`‘
`=
`
`N°ie= '
`This model only allows for convetsion of PBA to
`PAA to PAGN In the systemic (labeled ‘central‘)
`
`plasma compartment. Bioavailabiiity and drug
`effect is assume to relate directly to plasma
`metabolite concentatlons
`
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`Backgrou nd
`PAGH (PC-BL}
`
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`RIB. exponential
`
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`US 2010f0008859 A1
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`Jan. 14, 2010
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`METHODS OF TREATMENT USING
`AMNIONIA-SCAVE-.\'GlNG DRUGS
`
`CR( )S S-Rlil" l iI{l-iN(_‘l'i TO Rl-ll .A'l'l-ll.)
`Al’Pl..lC.4‘\'l‘I()NS
`
`[0001] This application claims benefit of priority to US.
`Provisional application Ser. No. 611093.234. filed Aug. 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. Ser. No. 6lt’0-48.830. filed on
`Apr. 29. 2008.
`
`TECHNICAL FIELD
`
`[0002] This invention relates to treatment of patients with
`nitrogen retention states. in particular urea cycle disorders
`(UC‘Ds} and cirrhosis complicated by hepatic encephalopathy
`(I-I13). using administered compounds that assist in elimina-
`tion 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 select-
`ing suitable dosages liar a patient.
`
`BACKG ROUND 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 ofphenylacetic acid (PAA). measuring the blood level
`ofthe prodrng
`Pl-3A) or of PAA formed Ii't‘n11 it is unre-
`liable. In addition. assessment oftreatment elfect by measur-
`ing 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 demon-
`strates that prodrugs oi‘ phcnylbutyric 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 UCl)s. It is particularly applicable to prodmgs
`that liberate or are n1el'al:Ioli;acd to form phenylacetic acid. i.e..
`prodrugs of PAA, and those prodrtigs that are nretabolized to
`fortn PBA.
`
`[0004] Hepatic encephalopathy refers to a spectrum o lineu-
`rologic 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
`FlCi. l. which also illustrates how certain ammonia-scaveng-
`ing dnigs act to assist in elimination of excessive ammonia.
`The enzymes including their Enzyme Connnission (EC)
`numbers and modes of inheritance include the following:
`[0006] Carbamyl phosphate synthetase (CPS: EC Num-
`ber 6.3 .4. I 6: autosomal recessive).
`[0007]
`ornithilte transcarbamylase (OTC:
`2.1.3.3; X-linked),
`
`l§i(_‘ Number
`
`argininosuccinate synthetase (ASS: EC‘ Number
`[0008]
`6.3.4.5: autosomal recessive),
`[0009]
`argininosuccinate lyase (ASL; EC Number 4 .3 ,2.
`1; autosomal recessive),
`[0010]
`arginase [AR(i: I€(.' Number 3.5.3.1: autosomal
`recessive). and
`[0011] N-acetyl glutamine synthetase (NAGS 1: EC
`Number 2.3.] .l : autosotnal recessive)
`[0012] Mitochondrial transporter deficiency states which
`mimic many features of urea cycle enzyme deficiencies
`include the following:
`[0013] Ornithine Lranslocase deficiency (hyperomithi11c-
`rnia. hyperammonemia. liomocitrullinuria or 111-111 Syn-
`drome)
`[0014] Citrin [aspartate glutamate transporter) defi-
`ciency
`[0015] The common feature of UC D and hepatic encepha-
`lopathy that render them treatable by methods of the inven-
`tion is an accumulation of excess waste nitrogen in the body.
`and llyperalnmonemia. In normal
`individuals.
`the body ’s
`intrinsic capacity for waste nitrogen excretion is greater than
`the 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 or HE. the body's intrinsic 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 up in the body ofa patient
`having a nitrogen retention disorder. and usually results in
`excess ammonia in the blood. This has various toxic eifects:
`dmgs that help eliminate the excess ammonia are an i1npor-
`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 retention states. dietary intake of pro-
`tein (a primary source of exogenous waste nitrogen) must be
`balanced by the patient’s ability to eliminate excess ammonia.
`Dietary protein can be limited. but a healthy diet requires a
`significant amount of protein. panicularly 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 [l1yperammonemia). The capacity
`to eliminate excess ammonia in treated patients can be con-
`sidered the sum of the 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. which is then excreted in urine and thus
`helps eliminate excess nitrogen.
`[0017] Based on prior studies in individual UCD patients
`[e.g. l3rusilow_. Pedirifric Research. vol. 29. I47-50 (1991);
`Brusilow and Finkelstien. .2’. Mefaboffsiti, vol. 42. 1336-39
`(1993)) in which 80-90% of the 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._. .2’. Pediatric-s, vol. 138. S56—S61
`(2001 )] or do not comment on the implications of incomplete
`conversion for dosing (e.g. Singh. Urea Cycle Disorders Con-
`
`17
`
`17
`
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`
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`
`

`
`US 201020008859 A1
`
`Jan. 14,2010
`
`ference Group ‘Consensus Starentem‘_fi'ort: a Corgfererice_for
`the Manageniem‘ QfPa£i'eirrs wr'.I':'r Urea Circle Disorders '.
`Suppl’ to J Pea't'afrf.c.'5. vol. l38[l ). S1-S5 [200] D.
`[0018] Current treatment guidelines reconunend 4 times
`per day dosing. based on the fact that l-‘BA is absorbed rapidly
`from the intestine when administered hr the form ofsodium
`PBA and exhibits a short half life ir1 the bloodstream (Urea
`Cycle Disorders Conference Group ‘Consensus Statement’
`200])
`(Turrent recommendations for sodium phenylbu-
`[0019]
`tyrale dosing indicate that dosage shottld not exceed 600
`mgfkg (for patients weighing up to 20 kg) or in any case 20
`grams total.
`
`DISCLOSURE OF EMBODIMENTS OF 'l'l-lli
`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-plrenylbutyr-ate]
`(I--IPN-100).
`based upon the urinary excretion of the drug metabolite phe-
`nylacetylglutamine (PAGN) andfor total urinary nitrogen. It
`is based in part on the discoveries that bioavailability of these
`drugs as conventionally assessed based on systemic blood
`levels of the drugs themselves or of the active species pro-
`duced i11 vivo from these drugs does not accurately predict
`removal of waste nitrogen or reduction ofplasma ammonia in
`healthy human volunteers. adults with liver disease. or
`patients with UCDs receiving ammonia scavenging drugs as
`defined below and that conversion of orally administered
`sodium phenylbutyrate (NaI’BA. or sodium PBA) to PAGN to
`urinary PAGN is incomplete. typically about 60—'F5“/u. Pro-
`drugs of phenylbutyrate (PISA.
`the active ingredient
`in
`BUPHENYUE {sodium phenylbutyrate), which is
`the
`sodium salt of PBA along with small amounts of inert ingre-
`dients), which is itself a prodrug ofphenylacetic acid (PAA).
`are especially subject to the eflects described herein.
`
`co3'r<a*
`
`pllenylbulymte
`OH
`
`0
`
`Fire n_\«'Ia.eclic acid
`NH;
`
`0
`
`'0'} N
`ll
`
`0
`
`Pltcliylcteetylglutmuinc
`
`[002]] 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, BUPHENYLITSJ (so-
`dium phenylbutyrate), AMM0N.1\PS®. butyroyloxymetl1yl-
`4-phenylbutyrate, glyceryl
`tri-[4-phenylbutyrate]
`(HPN-
`
`l 00). 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 ellicicntly to form pheuylacetyl glutarninc
`(PAGN ). PAGN is eflicicntly 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 BU PHE-
`NYLIEJ. and BUPHENYL*-Rt was used forthe Examples herein
`wherever test subjects were treated with sodium pl1enylbu-
`tyrate. Thus the sodium PBA dosages used in the Examples
`generally refer to a dosage of BUPHENYL-IEI. and the
`amounts of sodium phenylbutyrate in those Examples should
`be interpreted accordingly. Note that the terms ‘ammonia
`scavenger’ and ‘nitrogen scavenger‘ are used iriterchangeahly
`in this invention. reflecting the fact that the drugs described
`herein lower blood ammonia through elimination of waste
`nitrogen in the form ofPAGN.
`[0022]
`In some embodiments. the invention uses prodrugs
`that can be cortvcned into PAA within the body. Sodium
`phenylbutynate (sodium PBA) is one such drug; it is converted
`by oxidative mechanisms into PAA in the body. HPN-100 is
`another such drug: it cart be hydrolyzed to release PBA. which
`in tttrn can be oxidized to form PAA. Thus. HPN-100 is a
`prodrug of PISA. and also a prodrug of PAA. Clinical evi-
`dence demonstrates that llPN-100 is converted into FAA in
`the body as expected. and that PAA is then linked to a mo]-
`ecule ofglutamine and converted into PAGN. which is elin1i—
`nated in the urine as predicted. This process can be summa-
`rired as follows:
`HPN- l l'JIJ-*3 PB.-\ -*3 l’.-’\.-\
`
`PA.-\+giut.1rnirte—-PAGN.
`
`P!\(}N is mainly excreted iii the subject's urine. and
`[0023]
`removes two molecules ofamrnonia per molecule ofexcrctod
`PAGN. Each HPN- 1 00 molecule forms three PAA molecules.
`so each molecule of I-IPN-I 00 can promote excretion of six
`molecules ofarnrnonia. The clinical results suggest that con-
`version of HPN-10-0 into PBA and PAA is efficient and fairly
`rapid, but surprisingly suggest that some conversion of I-IPN
`to PAGN may occur before the IIPN-100 (or PBA. or FAA
`derived from PBA) enters systemic circulation. As a result.
`systemic levels of PAA or PBA are not reliably correlated
`with the ellicacy of HPN-J00 as an ammonia scavenger.
`[0024]
`ln some embodiments. the invention uses a prodrug
`of PBA. including HPN-100 and other esters of phenylbu-
`tyrate. The PBA prodrug is thus a prodrug ol‘a prodrug. since
`PBA acts to scavenge ammonia after it is converted to PAA
`and is thus considered a prodrttg of PAA. ].11 some embodi-
`rnents, the P13./\ prodrug is an ester of phenylbutyratc. such as
`those described below; a preferred PBA pi-odrug for use in the
`invention is HPN-100. These compounds can be made and
`used by methods disclosed in US. Pat. No. 5.968.979. which
`is incorporated herein by reference for its description ofthese
`compounds and methods for their administration.
`[0025] Where an ‘equal molar’ or ‘equimolar’ amount of a
`second drug is to be ttsed along with or instead of a certain
`amount of a first drug, the amount of each drug is calculated
`on a molar basis. and the equirnolar amount of the second
`drug is the amount that produces an equal molar amount of
`active drug in vivo. Where one of the drttgs is a prodrug. the
`amount ofprodrug will typically refer to the molar amount oi‘
`the active species Fortued from that prodrug. That active spe-
`cies is usually PAA for the prodrugs described herein, and the
`molar amount ofa prodrttg corresponds to the amount ol'PAA
`that would form in the body from that amount of the prodrug.
`assuming complete conversion imo PAA occurs in vivo.
`
`18
`
`18
`
`18 of39
`
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`
`

`
`US 201020008859 A1
`
`Jan. 14,2010
`
`Thus, for example. a molecule of HPN-l00 can be metabo-
`lized by ester hydrolysis followed by oxidation to fonn three
`molecules of PAA, so a mole of l-iPN~l0'0 would be consid-
`ered oquitnolar to three moles of PAA. Similarly. since I IPN-
`J00 hydrolyzes to form thrcc 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 I-Il’N- 1 00
`that correspond to equimolar amounts of certain relevant
`(loses of BUPI lliNYIJlt‘- (sodium pltenylbutyrate). Note that
`the conversion of the dose of sodium PBA to the dose of
`HPN—l00 involves correction for their different chemical
`
`forms [i.e. HPN-100 consists of glycerol in ester linkage with
`3 molecules of PBA and contains no sodium: [sodium PBA
`[g'[><0.95=I-IPN-100 [g] )] as well as correction for the specific
`gravity ofl-li-‘N-100. which is 1.1 g»’mL.
`
`BU-PIlEl\YL ®
`tsodium PEA}
`
`|ng"l>:gr'day
`4Sfi—t5t)I.I
`[patients '5 ‘ti kg]
`‘).9—13.I.r g.=':t12-‘day
`{patients : 20 kg!
`M-axiimnn Daily
`Dose: 20 g
`
`HI-‘N-1L'ILI FHA
`Equivntent
`Dose ting:
`
`l-IPN-lno PEA
`Equivalent
`Dose tmL}
`
`42B—5?L! 1ng."kg.'d.a_v
`
`0.39-0.52 n1l.»'kg.*day
`
`‘J.4—l2.4 g-"nt2a'dsy
`
`B.6—ll.2 rnL-"m2."da,v
`
`Maximum Daily
`Dose: 19 g
`
`I14 I11}.
`
`[0027] The present invention can use prodrugs of the for-
`mula (l):
`
`(1)
`
`1-1
`
`H
`
`H
`
`H
`
`It
`
`0-11,
`
`(J—P.»
`
`O—R3
`
`[0028] wherein R,. R2. and R3 are independently. H.
`
`§
`E
`
`,0 :{C H3 in
`O :{C trrH3m\-EJ
`
`or
`
`and n is zero or an even number_. III is an even
`[0029]
`number and at least one of R, . R3. and R3 is not H. For
`each R,_. R1. or R3. nor m is independently selected. so
`the R, . R2. and R3 groups in a compound of formula 1 do
`not have to be identical. The preferred compounds are
`those wherein none of R, . R3. and R3 is El. and fre-
`quently each n or n1 for a particular embodiment is the
`same, i.e.. R,, R2, and R3 are all the same. The advantage
`over the prior art of decreased dosage is greater with
`such Lriesters. and having all three acyl groups the same
`reduces issues related to mixtures of isomers. Moreover.
`
`the trio] backbone liberated by hydrolysis ofthe esters is
`glycerol. a normal constituent of dietary triglyceride
`which is non-toxic.
`
`[0030] The present invention also utilizes pltenylbutyrate
`and phenyiacetate prodrttgs of the forntttla II:
`
`0
`
`H.JJ\ K:
`
`(II:
`
`[0031] wherein R is a C,-Cm alkyl group.
`[0032] R4 is
`
`Of
`
`set-1,1,, S
`tC...H:....zi 3
`
`[0033]
`number.
`
`and n is zero or an even number, and m is an even
`
`in Formula II. R can be. for example. ethyl. propyl.
`[0034]
`isopropyl. n-butyl, and the like.
`[0035] The compounds of the invention are esters of the
`congeners of phenylalkanoic and phenylalkenoic acids hav-
`ing an even number of carbon atoms in the alkanoic acid
`porlittrt, which include pltenylacetic acid esters and those of
`phenylbntyric 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 :1 is 2 or
`4. the esters are also prodrngs for phenylhutyric acid. Prefer-
`ably the allcylene or alkenylene carboxylate group contains 24
`or fewer carbon atoms, so I: or in is less than 24. In some
`embodiments. n and m are 0. 2. 4 or 6, and in some preferred
`embodiments n or m is 2.
`
`[0036] Certain preferred embodiments ofthe invention use
`I-IPN-100 (Fomntla Ill):
`
`tIIIJ
`
`O
`
`0
`
`H
`H
`
`H
`
`H
`
`ii.
`
`O
`0
`
`0
`
`0
`
`[0037] Total daily dosage ofprodrugs like sodium PISA can
`often be selected according to the amount needed to provide
`
`19
`
`19
`
`19 of39
`
`19 of 39
`
`

`
`US 2010f0008859 A1
`
`Jan. 14,2010
`
`an appropriate amount of the active species. it‘ that amount is
`known or can be determined. PBA is a prodrng for PAA;
`therefore. an initial dose of PBA could be selected if an
`ellective dosage oft’./Uk were known. taking into account the
`fraction ofPl3A that is converted into PAA and ultimately into
`PAGN. if a subject has been treated with PAA or a prodrug
`that forms PAA in the body. the amount of the previously used
`drug that was efiective provides a possible starting point for
`selecting a dosage of a new prodrug of PAA. In this same
`patient, alter the new prodrug is administered at the expected
`PAA dose equivalence, the FAA levels in the subject could be
`monitored and the dose of the prodrug adjusted until tl1e same
`plasma level of PAA that was effective with the previous
`treatment is achieved. However. the current invention is based
`in part on finding that plasma PAA and PBA levels are not
`well correlated with the dose of a PBA prc-drug administered
`or with ammonia elimination: for tnonitoring a do sing level of
`a PBA prodrug, one should not rely upon these parameters to
`assess tl1e effectiveness of the prodrug. While not bound by
`the underlying theory. explanations for this effect [i.e. the
`inconsistent relationship between ammonia scavenging and
`PBA audfor PAA blood levels) are provided herein.
`[0038] The liallowing Table provides data from three clini-
`cal test groups showing the inconsistent relationship between
`plasma PAA and PBA levels among healthy volunteers.
`patients wit.l1 cirrhosis and UCI) patients. despite that fact
`that, as described in detail below, all groups exhibited similar
`annnonia scavenging activity based on ttrinary 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 nilrogell scaveng-
`ing drttg without being influenced by the many other factors
`that can affect plasma atnmonia levels.
`
`Plasma Pltrlrmacokinctics oI‘PB.-\. l’.»\.i\. and PAGN Coluparison across
`Studies
`
`Anal ytc
`
`Treatment
`
`6”“
`u.tgt'mLl
`
`‘l‘,m,,
`thl
`
`T‘/:
`Eh}
`
`.-‘\l..'(.‘,_,.
`tug ' h-"mLl
`
`PAA
`
`Healthy V"olu.r|tcers [Single Dose - 3 gr'm2:'day PBA Mole Equivalent]
`l’B.*\
`Sotliutu PBA
`221,0
`0.9
`0,?
`543.6
`I-IPl\'— 100
`3113
`2.4
`1.9
`132.2
`Soditun PB.-*1
`58.8
`3.9
`1.2
`2'i'£l.8
`H PN- llJt'I
`14.9
`4.0
`NC
`'.lI'J.9
`Sodium PB.-’\
`153.]
`3.2
`1.?
`395.1
`HPl\'— too
`30.2
`4-.t‘J
`NC
`262.1
`l'lt.'.‘.tllll._\-‘ \«'o|ur|tet:rs and (_‘irrI1otic Patients {ltJt'J rug.-‘kg BID!’
`
`PAGN
`
`PBA
`
`P.-\A
`
`PAGN
`
`1.2
`2.3
`42.8
`('ltiId—Pugl1.-\
`3.4
`2.9
`41.8
`(‘liild-Pugh B
`1.9
`3.l
`44.3
`Child-PtIgl1(‘
`2.1
`3.0
`29.8
`Voltmteers
`l .8
`3.8
`33.2
`Cl1ild~Pugh A
`2.8
`4.5
`3U,l$
`Cltild-Pttglt B
`'i'.i"
`4.3
`53.]
`Cliiltl-Pugh C‘
`1.9
`3.6
`25.5
`Volunteers
`5.0
`3.9
`37.?
`(‘ltild-Pugh A
`2.5
`4.0
`38.!
`(‘liilrl-Pugh B
`4.0
`5.3
`43.]
`Cl1ild—l’ugl1 C
`2,2’
`4.3
`46.3
`Volttnteers
`UCD Subjects tMu|tip1e Dose — PBA Mole Equivalent}
`
`131.?
`139.5
`I911
`132.?
`168.8
`252.4
`5?9.9
`130.5
`335.!
`466.99
`578.4
`fiSt'J.9
`
`PBA
`
`Sodium PEA
`l'l.PN- [U0
`
`141.0
`T'0.]
`
`2. I
`6.1
`
`NC
`NC
`
`?39_tJ
`54tJ.lI|
`
`-continued
`
`Pl-15l'I1:t Pliarnlacokinetics of PEA. PAA. and P.-\(.iN Cornparison across
`Studies
`
`.A.na|y‘tc
`PAA
`
`PAGN
`
`Treatment
`Sodium PBA
`HPN-1 IJIU
`Soditirrt FHA
`ll[’N—100
`
`(_‘,_,,_
`tug-"mLl
`53.!)
`40.5
`83.3
`?1.9
`
`‘I',,_,,,
`thl
`8.1
`8.0
`2.2
`8.0
`
`'1“ ’:
`(hi
`NC
`NC
`3.9
`4.8
`
`At;'(_‘9_,
`tug ' h*'mL}
`595.6
`5 ?4.6
`ll33.tJ
`1098.0
`
`(:,,m, -= niaxhnurn plastna c0I1eerrI.r3t ion:
`Tm, - time of maximum plasma concentration:
`_:\Ut’_‘3,, =.AL5C l'ro|n time (I to 24 hours:
`NF - not calcttlated
`'St'ut‘1y did not irtclttrle :1 sodium phertylhutyrate comp:1raIor.'trm_.v.1lLtes rep-
`resent l-lPN—1(It'J dosing only. AUC values represent the AUC trout time CI to
`the last Irtcastirahle [Jl.'1Sl1'|.:l conceal ration.
`
`[0039] One embodiment of the invention is a method for
`determining artdfor adjusting tl1e dose ofamrnonia scaveng-
`ing dmgs in patients with UCDs_. whereby dose would be
`based on the amount of dietary protein the patient is consum-
`ing. the anticipated percentage conversion of the drug to
`PAGN. and the patient’s residual urea synthetic capacity, if
`any. Dose adjustments. ifneccssary, would be based on the
`observed urinary excretion of PAGN andtor total urinary
`nitrogen (TUN), the difference between the two rellecting the
`patient’s endogenous capacity for waste nitrogen excretion
`This endogenous capacity may be absent in certain patients
`having innate ttnea cycle disorders dtte to inborn metabolic
`deficiencies. but patients with later-onset nitrogen accumula-
`tion disorders generally have some endogenous capacity,
`referred to sometimes as their residual urea synthesis capac~
`ity. See Brusilow. PROGRESS nc Ln-'Ett DISEASES. Ch. 12, pp.
`293-309 (1995). The subject's plasma ammonia level may
`also be detennined: this is a critical parameter for tracking
`elfectiveness of an overall treatment program. but reflects a
`variety of factors such as dietary protein and physiological
`stress. as well as the etlecl of a drug used to promote nitrogen
`excretion.
`
`[0040] Once the patient‘s residual endogenous capacity for
`waste nitrogen excretion has been determined. either as the
`dillerence between PAGN output and total nitrogen output or
`as total urinary nitrogen output in the absence ofan ammonia
`scavenging drug, the tolerable amount oldietary protein can
`be calculated for that patient according to the dosage of the
`ammonia scavenging drug being administered. or the dosage
`ofthe ammonia scavenging drugcan be adjusted orcalculated
`to compensate for an estimated protein intake.
`[0041] Another embodiment is a method tor determining
`and adjusting the dose of an ammonia scavenging drug to be
`administered to a patient with liver disease. including hepatic
`encephalopathy. whereby the starting dose would be based on
`the amount of dietary protein the patient is constuning, the
`anticipated conversion ofthe drug to PAGN. and the patit:t‘1[’S
`residual urea synthetic capacity. if any. While the urea syn-
`thetic capacity inpatients with liver disease would generally
`be greater than for patients with UCDs_. considerable patient
`to patient variability would be expected among both groups
`dependittg, respectively. on the severity of their liver disease
`and the severity of their inherited enzymatic defect. Dose
`adjustments based on the observed urinary excretion of
`PAGN and total waste nitrogen would adjust for these iridi-
`vidual patient characteristics.
`
`20
`
`20
`
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`
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`

`
`US 201020008859 A1
`
`Jan. 14, 2010
`
`[0042] Another embodiment is a method for determining or
`adjusting allowable dietary protein in the diet ofa patient with
`UCD or with hepatic encephalopathy. who is being treated
`with an oral FAA-fonning amrnnriia scavenging drug,
`whereby the amount of allowable protein would be deter-
`mined by the amount ofPAGN and total nitrogen in the urine.
`The difference between total 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 nitrogen processing capacity can be
`ttsed to adjust dietary protein intake while adnlitiistcring a
`lixed dosage ofan ammonia scavenging d