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`US 20100008859A1
`
`(19) United States
`(12) Patent Application Publication (10) Pub. N0.: US 2010/0008859 A1
`SCHARSCHMIDT
`(43) Pub. Date:
`Jan. 14, 2010
`
`(54) METHODS OF TREA’I‘A-IEN'I‘ USING
`AMMON Lx-SCAVENGING DRUGS
`
`(76)
`
`Inventor:
`
`Bruce SCHARSCIIMIDT. South
`
`San Francisco. (.‘A (US)
`
`Correspondence Address:
`MORRISON & FOERSTER LLI’
`12531 HIGH BLUFF DRIVE, SUITE 100
`SAN DIEGO, (TA 92130-2040 (US)
`
`(21) Appl. No:
`
`12,350,111
`
`(22)
`
`Filed:
`
`Jan. 7. 2009
`
`Related US. Application Data
`
`(60)
`
`Provisional application No. 6]!093.234. filed on Aug.
`29. 2008. provisional application No.
`film-48.830.
`filed on Apr. 29. 2008.
`
`Publication Classification
`
`(51}
`
`Int. (:1.
`(2006.01)
`A61K 49/00
`(2006.01)
`A61K 31/192
`(2006.01)
`AMP 13/00
`(52) US. (.‘l. ........................................ .. 4249.2; 5150568
`
`(57}
`
`ABSTRACT
`
`TIE: invention provides a method for determining a dose and
`schedule and making dose adjustments ot'PBA prodntgs used
`to treat nitrogen retention states. or ammonia accumulation
`disorders. by measuring ttrinary excretion o l‘ phenylacetyl-
`glulamine andr'or total urinary nitmgcn. The invention pro-
`vides methods to select an appropriate dosage o I‘ a PBA
`prodrug based on the patient‘s dietary protein intake. or based
`on previous treatments administered to the put ienl. The meth-
`ods are applicabie to selecting or modifying a dosing regimen
`tor a subject receiving an orally administered ammonia scav—
`enging drug.
`
`Sodium Phentybutyrate-
`v;
`
`. L
`
`UPIN EX. 1007
`
`1
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`20f39
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`Figure 1
`
`Sodium PhenleUtyrate-
`
` 2
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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-1OD or
`Buphenylo
`
`,................ ..l
`'
`'
`
`'
`Note:
`This model only allows for convetsion of PBA to
`PM to PAGN In the systemic (labeled ‘central‘l
`
`plaSma compartment. Bioavailability and drug
`effect is assume to relate directly to plasma
`metabolite concentatlons
`
`I. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`RIB. experiential
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`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . --.|
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`US 20102’0008859 Al
`
`Jan. 14, 2010
`
`METHODS OF TREATMENT USING
`AMMONIA-SCAVENGING DRUGS
`
`CR( )8 S-Rlil" l iRl-iNCi'i TO Rl-iI .A'l'l-il.)
`APPI..]C.“\'I‘IONS
`
`[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 “'l'rcating special populations having
`liver disease with nitrogen—scavenging compounds,“ naming
`Sharron Gargosky as inventor. Ser. No. 61t048.830. 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
`([113). using administered compounds that assist in elimina-
`tion of waste nitrogen from the body. The compotlnds can be
`orally administered small-molecule drugs. and the invention
`provides methods for delivering these compounds and select-
`ing suitable dosages for 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.
`I-lowever.
`the
`present invention is based on evidence that for certain pro-
`drugs ofphenylacetic acid (FAA). measuring the blood level
`ofthe prodrng
`PISA) or of PM formed from it is unre-
`liable. In addition. assessment oftreatment effect 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 invontiort demon-
`strates that prodrugs ol‘ 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 UCl)s. It is particularly applicable to prodrugs
`that liberate or are metabolized to form pllenylacetic acid. i.e..
`prodrugs of PAA. and those prodrngs that are metabolized to
`fortn PBA.
`
`[0004] Hepatic encephalopathy refers to a spectrum o l‘neu-
`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 front ammonia. The urea cycle is depicted in
`FlCi. 1. which also illustrates how certain ammonia-scaveng-
`ing dnigs act to assist itt elimination of excessive ammonia.
`The enzymes including their Enzyme Conuuission (EC)
`numbers and modes of inheritance include the following:
`[0006] Carbamyl phosphate synthetase (CPS: EC Num—
`ber 6.3.4.16: autosomal recessive).
`[0007]
`ornithine transcarhamylase (OTC: EC Number
`2.1.3.3; X-linked),
`
`argininosttccinate synthetase (ASS: EC Number
`[0008]
`6.3.4.5: autosomal recessive),
`[0009]
`argininosuccinate Iyase (ASL; EC Number 4 .3 .2.
`l; autosomal recessive),
`[0010]
`arginase {ARC}: IiC.‘ Number 3.5.3.1: autosomal
`recessive). and
`[0011] N-acetyl glutamine synthetase (NAGS 1: EC
`Number 2.3.] .l : autosomal recessive)
`[0012] Mitochondrial transporter deficiency states which
`mimic many features of urea cycle enzyme deficiencies
`include the following:
`[0013] Omitliine translocase deficiency (hyperomithinc-
`mia. hyperammonemia, homocitrullinuria 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 hyperammonemia. 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
`UC‘D 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 ltas various toxic elfects:
`dmgs that 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 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. 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 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 exoess 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 FAA 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
`(cg. Brusilow. Pediatric Research. vol. 29. 147-50 {1991);
`Brusilow and Finkelstien. J. Metabolism, vol. 42. 1336-39
`(1993)) in which 80-90% of the nitrogen scavenger sodium
`phenylbutyrale 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 (cg. Berry et al._. J. Pediatric-s, vol. 138. 856—861
`(2001 )) or do not comment on the implications of incomplete
`conversion for dosing (e.g. Singh. Urea (.‘ycle Disorders Con-
`
`17
`
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`

`US 201020008859 A1
`
`Jan. 14, 2010
`
`ferettce Group ‘Consensus Stareritentfl‘om a Conferencefor
`the Management of Patients with Urea Circle Disorders '.
`Suppl to J Pediatrics. vol. 138(1 ). Sl~SS (200] D.
`[0018] Current treatment guidelines reconunend 4 times
`per day dosing. based on the fact that PBA is absorbed rapidly
`frottt the intestine when administered in the form ofsodium
`PBA and exhibits a short half life itt tlte bloodstream (Urea
`Cycle Disorders Conference Group ‘Consensus Statement’
`200])
`[0019] Current recommendations for sodiunt phenylbu-
`tyrale dosing indicate tltat dosage should not exceed 600
`mgl'kg (for patients weighing up to 20 kg) or in any case 20
`grants total.
`
`DISCLOSURE OF EMBODIMENTS OF 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-
`butyratc and glyceryl
`tri-[4-phenylbtttyrate]
`(I--IPN-100).
`based upon the ttrinary excretion of the drug metabolite phe-
`ttylacetylglutatttine (PAGN) andr'or 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 itt vivo from these drugs does not accurately predict
`removal of waste nitrogen or reduction ol'plasma 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 (NaPBA. or sodium PBA) to PAGN to
`urinary PAGN is incomplete. typically about 60-75%. Pro-
`drugs of phenylbutyrate (PBA.
`the active ingredient
`in
`BUPHENYL® {sodium phettylbutyrate), which is
`the
`sodium salt of PBA along with small amounts of inert ingre-
`dients), which is itself a prodrug of phenylacetic acid (FAA).
`are especially subject to the efl'ects described herein.
`
`(:0th
`
`phenylbulymtc
`OH
`
`0
`
`File nylaileic acid
`NH}
`
`0
`
`110
`
`Pltcnylaectylglutmuinc
`
`[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, BUPHENYLIE'J (so-
`dium phenylbutyrate). AMMONAPSGL'. butymyloxymethyl-
`4-phenylbtttyrate, glyceryl
`tri-[4-phenylbutyrate]
`(l-lPN-
`
`100). esters. ethers. and acceptable salts. acids attd derivatives
`thereof. These drugs reduce high levels of endogenous
`ammonia by providing phenylacetic acid in vivo. which is
`metabolixed efficiently to form phenylaeetyl glutaminc
`(PAGN ). PAGN is efficiently excreted in urine. carrying away
`two equivalents of nitrogen per mole of PAA converted to
`I’AGN. References herein to sodiunt phenylbutyrate are
`understood to include reference to the drug product BU Pi—IE-
`NYLIEJ. and BUPEIENYLth was used fortlte Examples herein
`wherever test subjects were treated with sodium phenylth-
`tyrate. Thus the sodium PBA dosages used in the Examples
`generally refer to a dosage of BUPHENYLtEI. attd the
`amounts of sodium phenylbutyrate itt those Examples should
`be interpreted accordingly. Note that the terms ‘ammonia
`scavenger’ and ‘nitmgcn scavenger' are used interchangeably
`itt 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 convened into PA.‘\ within the body. Sodium
`phenylbutyrate (soditu‘n PBA) is one such drug; it is convened
`by oxidative mechanisms into FAA in the body. HPN-lOO is
`anotlter such drug: it catt be hydrolyzed to release PBA. which
`itt tttrn can be oxidized to form PAA. Thus. [JPN-100 is a
`prodrug of PISA. and also a prodrug of PAA. Clinical evi-
`dence demonstrates that llPN-IOO is converted into FAA in
`the body as expected. and that PAA is then linked to a mo]—
`ecule ofglutamitte and converted into PAGN. which is elittti—
`nated in the urine as predicted. This process can be summa-
`rired as follows:
`HPN- l I'M-*3 PBA *3 FAA
`
`PMs-glutamine—WAGN.
`
`PAGN is mainly excreted iii the subject's urine. and
`[0023]
`removes two molecules of ammonia per molecule ofexcrctod
`PAGN. Each HPN- l 00 molecule forms three FAA molecules.
`so eaclt molecule of I-IPN-l 00 catt promote excretion of six
`molecules of antmonia. The clinical results suggest that con-
`version of HPN- l 00 into l’BA and FAA is efficient and fairly
`rapid, but surprisingly suggest that some conversion of I-lPN
`to PAGN may occur before the IIPN-IOO (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 efficacy of HPN-JOO as an ammonia scavenger.
`[0024]
`In some embodiments. the invention uses a prodrug
`of PBA. including HPN-IOO 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 prodrug of PAA. In some embodi—
`ments, the PBA prodmg is an ester ofphcnylbutyratc. such as
`those described below; a preferred PBA prodrug for use in the
`invention is HPN-IOO. 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 used 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 equimolar amount of the second
`drug is the amount that produces an equal molar amount of
`active drug in vivo. Where one of the drugs is a prodrug. the
`autount ol‘prodrug will typically refer to the molar antount of
`the active species formed from that prodrug. That active spe-
`cies is usually PAA for the prodrugs described herein, and the
`molar amount ofa prodrug corresponds to the amount ofPAA
`that would form in the body front that amount of the prodrug.
`assuming complete conversion into PAA occurs in vivo.
`
`18
`
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`
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`
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`

`US 201020008859 A1
`
`Jan. 14, 2010
`
`Thus, for example. a molecule of HPN-lOO 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 oquimoiar to three moles of PAA. Similarly. since I IPN-
`100 hydrolyzes to form three molecules of FHA [and one
`molecule of glycerin). an equimolar amount of HPN-IOO
`would be one-third of the molar amount of PBA.
`
`[0026] The following 'I'able sets forth amounts of I-IPN- l 00
`that correspond to equimolar amounts of certain relevant
`doses of BUPl lliNYIJ-R‘: (sodium pltenylbutyratc). 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-IOO consists of glycerol in ester linkage with
`3 molecules of PBA and contains no sodium: [sodium PBA
`[g]x0.95=I-IPN-100 [g] )] as well as correction for the specific
`gravity of [JPN-100. which is 1.1 gme.
`
`BUPIIEBYL ®
`tsodium PEA}
`
`450-600 lug-'kgr'dsy
`[patients "-2 3:] kg]
`93—131! g.-"ntZ-’day
`{patients a 20 kg!
`Maximum Daily
`Dose: 20 g
`
`HPN- 1 DU PBA
`Equivalent
`Dose ting:
`
`HP‘N- ] no PEA
`Equivalent
`Dose {mL}
`
`IDS—STU mg."kg-'d.ay
`
`0.39-0.52 niiJkgfdsy
`
`9.4414 g-"ntli'dsy
`
`13.6—11.2 mL-"ml-‘dsy
`
`Maximum Daily
`Dose: 19 g
`
`HA 1111.
`
`[0027] The present invention can use prodrugs of the for-
`mula (l):
`
`(1)
`
`1-1
`
`H
`
`H
`
`H
`
`It
`
`0—11.
`
`{J—Rn
`
`0—11;
`
`[0028] wherein R1. R2. and R3 are independently. H.
`
`{C H3)”
`
`or
`
`at) :{C “HEM-2i
`
`and n is zero or an even number, m is an even
`[0029]
`number and at least one of R l . R3. and R3 is not H. For
`each R1, R1. or R3. nor in is independently selected. so
`the R1 . R2, and R3 groups in a compound of formula 1 do
`not have to be identical. The preferred compounds are
`those wherein none of R1. R3. and R3 is ll. and fre-
`quently each n or n1 for a particular embodiment is the
`same. i.e.. R1. 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 phenyiacctate prodrngs of the formula II:
`
`0
`
`HAL it.
`
`(II!
`
`[0031] wherein R is a C‘l-Cm alkyl group.
`[0032] R4 is
`
`or
`
`«SI-12),, :
`lle'lzm—zl :
`
`[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
`portion, which include phenylacetic acid esters and those of
`phenylbutyric acid. etc.. which can be converted by efl'icient
`beta-oxidation processes to phenylacetic acid in the body.
`They are thus prodrugs for phenylacetic acid. Where It is 2 or
`4. the esters are also prodrugs for phenylhutyric acid. Prefer-
`ably the alkylene or alkcnylene carboxylate group contains 24
`or fewer carbon atoms, so I: or m 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-lPN-100(Fomtttla Ill):
`
`[III]
`
`0
`
`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
`
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`
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`

`

`US 2010211008859 A1
`
`Jan. 14, 2010
`
`an appropriate amount of the active species. if that amount is
`known or can be determined. PBA is a prodrng for FAA;
`therefore. an initial dose of PBA could be selected if an
`elTective desage ofPAA Were known. taking into account the
`fraction ofPBA that is converted into PAA and ultimately into
`PAGN. If a subject has been treated with PAA or a prodrug
`that forms FAA in the body. the amount of the previously used
`drug that was efl'ective provides a possible starting point for
`selecting a dosage of a new prodrug of PAA. In this same
`patient, alter the new pmdnig is administered at the expected
`FAA dose equivalence, the FAA leVels in the subject could be
`monitored and the dose of the prodrug adjusted until the 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 FAA and PBA levels are not
`well correlated with the dose of a PBA pro-drug administered
`or with ammonia elimination: for monitoring a do sing level of
`a PBA prodrug. one should not rely upon these parameters to
`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
`PBA andfor PAA blood levels) are provided herein.
`[0038] The lollowing Table provides data from three clini-
`cal test groups showing the inconsistent relationship between
`plasma FAA and PBA levels among healthy volunteers.
`patients with cirrhosis and UCI) patients. despite that fact
`that, as described in detail beiow, 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 Pharmacokirletics oI‘PBA. FAA. and PAGN Comparison across
`Studies
`
`Anal yte
`
`Treatment
`
`cm”
`urgile
`
`Tm,r
`thl
`
`TV:
`th}
`
`sue...
`[its ' h-"le
`
`PM
`
`Healthy Volunteers [Single Dose - 3 gr'mzr'day PBA Mclc Equivalent]
`PBA
`Sodium PEA
`221,0
`0.9
`0,?
`542.6
`I-IPN— [00
`32.0
`2.4
`1.9
`E312
`Soditun PBA
`58.8
`3.9
`1.2
`229.8
`H PN— [00
`14.9
`4.0
`NC
`mg
`Sodium PEA
`63.1
`3.2
`1.7
`395.1
`HPN— [no
`30.2
`4.0
`NC
`262.l
`Healthy Volunteers and (.‘irrliolie Patients [[00 nigfikg BlDt'
`
`PAGN
`
`PBA
`
`FAA
`
`PAGN
`
`1.2
`2.3
`42.8
`Child—Pugh A
`3.4
`2.9
`41.8
`Child-Pugh B
`1.9
`3.l
`44.3
`ChilvaughC
`2.1
`3.0
`29.8
`\bllmteers
`l .8
`3.8
`33.2
`Child~Pugh A
`2.8
`4.5
`30.8
`Child—Pugh B
`2.?
`4.8
`53.1
`Child-Pugh C
`1.9
`3.6
`25.5
`Volunteers
`5,0
`3.9
`31?
`Child-Pugh A
`15
`4.0
`38.1
`Child-Pugh B
`4.0
`5.3
`43.]
`Child—Pugh C
`12
`4.3
`46.3
`Volunteers
`UCD Subjects tMultiple Dose — PBA Mole Equivalent}
`
`[31.2
`[89.5
`I93.l
`132.?
`168.8
`252.4
`578.9
`L305
`335.!
`466.99
`528.4
`550.9
`
`PBA
`
`Sodium PEA
`HPN- [00
`
`141.0
`'30.]
`
`2. I
`6.1
`
`NC
`NC
`
`?39_U
`540.0
`
`-continued
`
`Plasma Phamlacokineties of PEA. FAA. and PAGN Comparison at:is Studies
`
`Analy‘te
`PAA
`
`PAGN
`
`Treatment
`Sodium PBA
`HPN-100
`Sodium PBA
`llPN—100
`
`cm
`tug-"mt:
`53.0
`40.5
`83.3
`T13
`
`TM,
`th]
`8.l
`8.0
`2.3
`8.0
`
`'1‘l :
`(h)
`NC
`NC
`3.9
`4.8
`
`soc“
`tug - htle
`595.6
`5 i413
`“33.0
`1098.0
`
`Cum -= maximum plasma concennat ion:
`Tm; - time of maximum plasma concentration:
`AUCM =AL5C from lime (I to 24 hours:
`NF - not calculated
`'St'ut‘ly did not include :1 sodium phenylhnlyrate comparslornrm. values rep-
`resent l-lPN- 100 dosing billy. AUC values represent the AUC from time 0 to
`the lasr measurable plasma concenl ration.
`
`[0039] One embodiment of the invention is a method for
`determining andfor adjusting the dose of ammonia 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. il‘necessary. would be based on the
`observed urinary excretion of PAGN andr'or total urinary
`nitrogen (TUN), the difference between the two reflecting the
`patient’s endogenous capacity for waste nitrogen excretion.
`This endogenous capacity may be absent in certain patients
`having imiate Luca cycle disorders due 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~
`iry. See Brusilow. PROGRESS nx' LIVER DISEASES, Ch. 12, pp.
`293-309 {1995]. The subject‘s plasma ammonia level may
`also be detennined: this is a critical parameter for tracking
`eifectiveness of an overall treatment program. but reflects a
`variety of factors such as dietary protein and physiological
`stress. as well as the etTect 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
`diITerence between PAGN output and total nitrogen output or
`as total urinary nitrogen output in the absence ofan ammonia
`scavenging drug, the tolerable amount oi‘dietary protein can
`be calculated for that patient according to the dosage of the
`ammonia scavortging 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 detennining
`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
`Lhe amount of dietary protein the patient is consmning. the
`anticipated conversion ol‘the drug to PAGN. and the patient’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 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 indi-
`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
`adj listing allowable dietary protein in the diet ofa patient with
`UCD or with hepatic encephalopathy. who is being treated
`with an oral FAA-tonnng ammonia scavenging drug.
`whereby the amount of allowable protein would be deter-
`mined by the amottnt ofPAGN and total nitrogen in the urine.
`The difl'erence between total waste nitrogen in the urine and
`the amount of PAGN excreted is indicative of the patient ‘5
`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 administering a
`fixed dosage ofan ammonia scavenging drug. or the dosage of
`the ammonia scavenging drug can be determined according to
`the amount needed to facilitate elimination ofthe waste nitro-
`gen liont the 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, which results from the P.’\.‘\-forrning
`ammonia scavenging drug being administered. When making
`these calculations or adjustments, it is suitable to assume that
`about 4l% of nitrogen in protein will become waste nitrogen
`that needs to be excreted in the urine (the amount may be less
`for growing patients. who retain a greater fraction of ingested
`nitrogen to suppon body growth). and that about 16% of
`protein, on average, is nitrogen (see Brusilow 1991).
`[0043]
`11 has generally been assumed for such determina-
`tions that a prodrug would be converted with 100% efficiency
`into PAGN lbrclimination [see e.g.. Berry et al..JC Pediatrics
`138(1). 856-561 (2001)wherel’1(}. 1 assumes 100% conver-
`sion]; and one report found that about 80-90% ofPAA or PBA
`was excreted from a specific individual as PAGN. Brusilow.
`Pediar