as) United States
`a2) Patent Application Publication 0) Pub. No.: US 2010/0008859 Al
`Jan. 14, 2010
`SCHARSCHMIDT
`
`US 2010000885941
`
`(43) Pub. Date: METIIODS OF TREATMENT USING
`
`(54)
`
`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
`(52) US. CMe ceecssssssssssssssssvssvssessssesssseese 424/9.2; 514/568
`(57)
`ABSTRACT
`
`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 phenylacetyl-
`glutamine and/or total urinary nitrogen. ‘lhe invention pro-
`vides methods to select an appropriate dosage of a PBA
`prodrug basedon the patient’s dietary protein intake, or based
`on previous treatments administered to the patient. The meth-
`ods are applicable to selecting or modifying a dosing regimen
`for a subject receiving an orally administered ammonia scav-
`enging drug.
`
`NH’,
`
`Sodium Phenlybutyrate.
`¥_
`
`
`FOenecateninsSe
`
`*.
`
`
`
`
`Fumarate
`
`Par Pharmaceutical, Inc. Ex. 1004
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 1 of 39
`
`

`

`Patent Application Publication
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`Jan. 14, 2010 Sheet 1 of 15
`
`US 2010/0008859 Al
`
`Figure 1
`
`Sodium Phenlybutyrate
`
`NH’,Glutamate)__»Ghtamioa_(Poemlctas
`
`v
`cineexoretion
`
`jTonenacereece
`
`
`
`Par Pharmaceutical, Inc. Ex. 1004
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 2 of 39
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`

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`Patent Application Publication
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`Jan. 14, 2010 Sheet 2 of 15
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`US 2010/0008859 Al
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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-
`
`Note:
`-HPN-100 or
`This model only allows for conversion of PBA to
`Buphenyl®
`PAA to PAGN in the systemic (labeled ‘central’)
`
`Oral|Dose . deh
`
`plasma compartment. Bioavailability and drug
`gocgeeeeeeeeeeey
`i
`:
`effect is assumeto relate directly to plasma
`metabolite concentations
`
`
`
` Covariate
`
`BSA/1.73 x VM1, VM2, VPB, VPA, VPG
`
`
`
`Par Pharmaceutical, Inc. Ex. 1004
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 3 of 39
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`Par Pharmaceutical, Inc. Ex. 1004
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
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`Par Pharmaceutical, Inc. Ex. 1004
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`Par Pharmaceutical, Inc. Ex. 1004
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`Jan. 14,2010 Sheet 12 of 15
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`ar Pharmaceutical, Inc. Ex. 1004
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`US 2010/0008859 Al
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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 referencein 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 Gargoskyas 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 compoundsthatassist in elimina-
`tion of waste nitrogen fromthe body. The compounds can be
`orally administered small-molecule drugs, and the invention
`provides methods for delivering these compoundsandselect-
`ing suitable dosages fora patient.
`
`BACKGROUNDART
`
`
`
`argininosuccinate synthetase (ASS; EC Number
`[0008]
`6.3.4.5; autosomalrecessive),
`
`[0009]
`argininosuccinate lyase (ASL; EC Number4.3.2.
`1; autosomalrecessive),
`[0010]
`arginase (ARG; EC Number3.5.3.1; 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] Ornithinetranslocase deficiency(hyperomithine-
`mia, hyperammonemia, homocitrullinuria or III Syn-
`drome)
`[0014] Citrin (aspartate glutamate transporter) defi-
`ciency
`[0015]
`‘The commonfeature of UCD and hepatic encepha-
`opathy that render them treatable by methods of the inven-
`ion 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
`he body’s waste nitrogen production, so waste nitrogen does
`not accumulate and ammonia does not build up to harmful
`evels. For patients with nitrogen retention states such as
`UCDor HE,the body’sintrinsic capacity for waste nitrogen
`excretion is less than the body’s waste nitrogen production
`based on a normaldict that contains significant amounts of
`[0003] Drug dosingis usually based upon measurement of
`protein. Asaresult, nitrogen builds up in the body ofa patient
`blood levels of the active drug species in conjunction with
`having a nitrogen retention disorder, and usually results in
`excess ammonia in the blood. This has various toxic effects;
`clinical assessment of treatment response. However,
`the
`present invention is based on evidence that for certain pro-
`drugs that help eliminate the excess ammonia are an impor-
`drugs of phenylacetic acid (PAA), measuring the blood level
`ant part of an overall managementstrategy for such disor-
`ders.
`of the prodrug (e.g. PBA) or of PAA formed fromit is unre-
`liable. In addition, assessment of treatment effect by measur-
`To avoid build-up of ammonia to toxic levels in
`[0016]
`ing levels of ammoniain the bloodis inconvenient, becauseit
`patients with nitrogen retention states, dietary intake of pro-
`requires withdrawing multiple blood samples undercarefully
`ein (a primary source of exogenouswaste nitrogen) must be
`controlled conditions. Because blood ammonia levels are
`balanced bythe patient’s ability to climinate excess ammonia.
`affected byvarious factors including dietaryprotein, theyalso
`Dietary protein can be limited, but a healthy diet requires a
`fail to provide a direct measure of how much ammonia the
`significant amount of protein, particularly for growing chil-
`drug is mobilizing for elimimation. lhe invention demon-
`dren; thus in addition to controlling dietary protein intake,
`strates that prodrugs of phenylbutyric acid (PBA) behave
`drugs that assist with elimination of nitrogen are used to
`similarly to sodium PBA, in that measuring PBA levels is
`reduce ammonia build-up (hyperammonemia). The capacity
`unreliable for assessing their effectiveness. This invention
`to eliminate excess ammonia in treated patients can be con-
`provides a novel method for dosing in patients with nitrogen
`sidered the sum of the patient’s endogenous capacity for
`retention states, in particular patients with liver disease and
`nitrogen elimination (if any) plus the amount of additional
`clinical manifestations of hepatic encephalopathy and
`nitrogen-elimination capacity that is provided by a nitrogen
`patients with UCDs. It is particularly applicable to prodrugs
`scavenging drug. The methodsofthe invention use a variety
`thatliberate or are metabolized to form phenylacetic acid, i.e.,
`of different drugs that reduce excess waste nitrogen and
`prodrugs of PAA,and those prodrugsthat are metabolized to
`ammonia by converting it to readily-excreted forms, such as
`form PBA.
`phenylacety] glutamine (PAGN). In some embodiments, the
`[0004] Hepatic encephalopathyrefers to a spectrumofneu-
`invention relates to methods for determining or adjusting a
`rologic signs and symptoms which frequently occur in
`dosage of an oral drug that forms PAA in vivo, which is
`patients with cirrhosis or certain other typesofliver disease.
`converted into PAGN,whichis then excreted in urine and thus
`[0005] Urea cycle disorders comprise several
`inherited
`helps eliminate excess nitrogen.
`deficiencies of enzymes or transporters necessary for the
`[0017] Based onprior studies in individual UCDpatients
`synthesis of urea from ammonia. Theurea cycle is depicted in
`(e.g. Brusilow, Pediatric Research, vol. 29, 147-50 (1991);
`FIG. 1, whichalsoillustrates how certain ammonia-scaveng-
`Brusilow and Finkelstien, . Metabolism, vol. 42, 1336-39
`ing drugsact to assist in elimination of excessive ammonia.
`(1993)) in which 80-90% of the nitrogen scavenger sodium
`The enzymes including their Enzyme Commission (EC)
`phenylbutyrate was reportedly excreted in the urine as PAGN,
`numbers and modesof inheritance include the following:
`current treatment guidelinestypically cither assume complete
`[0006] Carbamy1 phosphate synthetase (CPS; EC Num-
`conversion of sodium phenylbutyrate or other PAA prodrugs
`ber 6.3.4.16; autosomalrecessive),
`to PAGN(e.g. Berryet al., J. Pediatrics, vol. 138, 856-861
`
`[0007]
`ornithine transcarbamylase (OTC; EC Number
`(2001)) or do not comment onthe implications ofincomplete
`2.1.3.3; X-linked),
`conversion for dosing (e.g. Singh, Urea Cycle Disorders Con-
`
`Par Pharmaceutical , Inc. Ex. 1004
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 17 of 39
`
`

`

`US 2010/0008859 Al
`
`Jan. 14, 2010
`
`ference Group ‘Consensus Statementfrom a Conferencefor
`the Management ofPatients with Urea Cycle Disorders’,
`Suppl to J Pediatrics, vol. 138(1), 81-S5 (2001)).
`[0018] Current treatment guidelines recommend 4 times
`per day dosing, based onthe fact that PBA is absorbed rapidly
`from the intestine when administered in the form of sodium
`PBAand exhibits a short half life 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 EMBODIMENTS OFTHE
`
`INVENTION
`
`[0020] The invention provides a novel approachfor deter-
`mining and adjusting the schedule and doseof orally admin-
`istered nitrogen scavenging drugs, including sodium phenyl-
`butyrate and glyceryl
`tri-[4-phenylbutyrate]
`(HPN-100),
`based uponthe urinary excretion of the drug metabolite phe-
`nylacetylglutamine (PAGN)and/or total urinary nitrogen.It
`is basedin part onthe discoveries thal bioavailability of these
`drugs as conventionally assessed based on systemic blood
`levels of the drugs themselves or ofthe active species pro-
`duced in vivo from these drugs does not accurately predict
`removalofwaste 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
`BUPHENYT.® (sodium phenylbutyrate), which is
`the
`sodium salt of PBA along with small amountsofinert ingre-
`dients), which is itself a prodrug of phenylacetic acid (PAA),
`are especially subject to the effects described herein.
`
`‘COyNa*
`
`phenylbutyrate
`OIL
`
`oO
`
`Phenylacetic acid
`NH
`
`O.
`
`Phenylacetylglutamine
`
`[0021] As used herein “ammonia scavenging drugs” is
`defined to include all orally administered drugsin 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
`tri-[4-phenylbutyrate]
`(HPN-
`
`
`
`100), esters, ethers, and acceptable salts, acids and derivatives
`hereof. These drugs reduce high levels of endogenous
`ammonia byproviding phenylacetic acid in vivo, which is
`metabolized efficiently to form phenylacetyl glutamine
`(PAGN). PAGNisefficiently excreted in urine, carrying away
`two equivalents of nitrogen per mole of PAA converted to
`PAGN. References herein to sodium phenylbutyrate are
`understoodto include reference to the drug product BUPHE-
`
`NYL®, and BUPHENYL®wasused for the Examples herein
`wherever test subjects were treated with sodium phenylbu-
`tyrate. Thus the sodium PBA dosagesused in the Examples
`
`generally refer to a dosage of BUPHENYL®, and the
`amounts of sodium phenylbutyrate in those Examples should
`be interpreted accordingly. Note that the terms ‘ammonia
`scavenger’ and‘nitrogen scavenger’are used interchangeably
`in this invention, reflecting the fact that the drugs described
`herein lower blood ammonia through elimination of waste
`nitrogen in the form of PAGN.
`[0022]
`In some embodiments, the invention uses prodrugs
`hat can be converted into PAA within the body. Sodium
`pheny!butyrate (sodium PBA)is one suchdrug; it is converted
`by oxidative mechanisms into PAA in the body. IIPN-100is
`another such drug: 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
`he body as expected, and that PAAis then linked to a mol-
`ecule of glutamine and converted into PAGN,which is elimi-
`nated in the urine as predicted. This process can be summa-
`rized as follows:
`HPN-100--3PBA—*3PAA
`
`PAA+glutamine—PAGN.
`
`PAGNis mainlyexcreted in the subject’s urine, and
`[0023]
`removes two molecules of ammonia per molecule of excreted
`PAGN.Each HPN-100 molecule forms three PAA molecules,
`so each molecule of HPN-100 can promote excretion of six
`molecules of ammonia. The clinical results suggest that con-
`version of HPN-100 into PBA and PAAisefficient andfairly
`rapid, bul 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 after it is converted to PAA
`and is thus considered a prodrug of PAA. In some embodi-
`ments, the PBA prodrugis an ester ofphenylbutyrate, such as
`those described below; a preferred PBA prodrugforuse in the
`invention is IIPN-100. These compounds can be made and
`used by methods disclosed in U.S. Pat. No. 5,968,979, which
`is incorporated herein by referenceforits description ofthese
`compounds and methodsfor their administration.
`[0025] Where an ‘equal molar’ or ‘equimolar’ amountof a
`second drug is to be used along with or instead of a certain
`amountofa first drug, the amount of each drugis 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 oneof the drugs is a prodrug, the
`amountofprodrug will typicallyrefer to the molar amount of
`the active species formed from that prodrug. Thatactive spe-
`cies is usually PAAfor the prodrugs described herein, and the
`molar amount ofa prodrug correspondsto the amount ofPAA
`that would form in the bodyfrom that amountofthe prodrug,
`assuming complete conversion into PAA occurs in vivo.
`
`Par Pharmaceutical , Inc. Ex. 1004
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 18 of 39
`
`

`

`US 2010/0008859 Al
`
`Jan. 14, 2010
`
`3
`
`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 IIPN-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 ofcertain relevant
`doses of BUPHENYL®(sodiumphenylbutyrate). 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 glycerol in ester linkage with
`3 molecules of PBA and contains no sodium; (sodium PBA
`[g]x0.95=IIPN-100 [g])] as well as correction for the specific
`gravity of HPN-100, whichis 1.1 g/mL.
`
`the triol backboneliberated by hydrolysis ofthe esters is
`glycerol, a normal constituent of dietary triglyceride
`which is non-toxic.
`[0030] The present invention also utilizes phenylbutyrate
`and phenylacetate prodrugs of the formula II:
`
`(1)
`
`R—o
`
`Oo
`
`Ry
`
`[0031] wherein R is a C,-C,, alkyl group,
`[0032] R,is
`
` HPN-100PBA HPN-100PBAx<)BUPHENYL ®
`
`
`
`Equivalent
`Equivalent
`Tose (m1.)
`Dase (mg)
`428-570 mo/ke/day —0.39-0.52 mL/ke/day
`
`(CH),
`
`or
`
`(sodium PBA)
`450-600 mo/ke/day
`(patients = 20 kg)
`9.9-13.0 gim2/day
`(patients > 20 ke)
`Maximum Daily
`Dose: 20 g
`
`94-124 g/m2/day
`
`8.6-11.2 mL/m2/day
`
`Maximum Daily
`Dose: 19 g
`
`17.4 mL
`
`a
`.
`.
`.
`.
`‘he present invention can use prodrugsofthe for-
`
`[0027]
`mula(1):
`
`@
`
`H
`
`O—R
`
`[0028] wherein R,, R,, and R, are independently, H.
`
`Hi)2K
`
`oO
`
`or
`
`(CoH2m-2)
`
`and n is zero or an even number, mis an even
`[0029]
`numberandat least one of R,, R,, and R, is not H. For
`each R,, R,, or R;, n or mis independently selected, so
`the R,, Ro, andR, groups ina compoundof formula I do
`not have to be identical. The preferred compoundsare
`those wherein none of R,, R;, and R; is H, and fre-
`quently cach n or m for a particular embodimentis the
`same, i.e., R,,R,,andR,are all the same. The advantage
`over the prior art of decreased dosage is greater with
`suchtriesters, and having all three acyl groups the same
`reducesissues related to mixtures of isomers. Moreover,
`
`,
`J
`(CoH2m.2)
`
`.
`.
`and nis zero or an even number, and mis an even
`
`[0033]
`number.
`In FormulaII, R can be, for example, ethyl,
`0034]
`propyl,
`|
`]
`,
`°
`Pie,
`tay" PYOPY!s
`isopropyl, n-butyl, andthelike.
`[0035] The compoundsof 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, cte., which can be converted by efficient
`beta-oxidation processes to phenylacctic acid in the body.
`Theyare thus prodrugs for phenylacetic acid. Wheren 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 m is less than 24. In some
`embodiments, n and m are 0, 2, 4 or 6, and in somepreferred
`embodiments n or m is 2.
`[0036] Certain preferred embodimentsofthe invention use
`IIPN-100 (formula IIT):
`
`ait)
`
`Oo
`
`H
`
`H
`
`H
`H
`
`H
`
`0
`
`oO
`9
`
`0,
`
`dé
`
`[0037] Total daily dosage ofprodmgslike sodium PBA can
`often be selected according to the amount neededto provide
`
`Par Pharmaceutical, Inc. Ex. 1004
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 19 of 39
`
`

`

`US 2010/0008859 Al
`
`Jan. 14, 2010
`
`an appropriate amountofthe active species, if that amountis
`knownor 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,taking into accountthe
`fraction ofPBAthat is converted into PAA and ultimatelyinto
`PAGN.If a subject has been treated with PAA or a prodrug
`that forms PAA in the body, the amount ofthe previously used
`drug that was effective provides a possible starting point for
`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 doscofthe prodrug adjusted until 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 PBA levels are not
`well correlated with the dose of a PBA prodrug administered
`or with ammonia elimination; for monitoring a dosing level of
`a PBAprodrug, one should notrely 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
`PBAand/or PAA bloodlevels) are provided herein.
`[0038] The following Table provides data from three clini-
`cal test groups showingtheinconsistentrelationship between
`plasma PAA and PBA levels among healthy volunteers,
`patients with cirrhosis and UCD patients, despite that fact
`that, as described in detail 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 bythe administered nitrogen scaveng-
`ing drug without being influenced by the many other factors
`that can affect plasma ammonialevels.
`
`Plasma Pharmacokinetics ofPBA, PAA, and PAGN Comparison across
`Studies
`
`Analyte
`
`Treatment
`
`Chax
`(uigymL)
`
`Vinax
`(bh)
`
`14
`(bh)
`
`AUCo4
`(ug: LhimL)
`
`-continued
`
`Plasma Pharmacokinetics of PBA, PAA, and PAGN Comparison across
`Studies
`
`Analyte
`PAA
`
`AUC24
`Ti
`Tnax
`Cmax
`(yg > h’mL)
`(h)
`(h)
`(ug/mL)
`‘Treatment
`595.6
`NC
`8.1
`53.0
`Sodium PBA
`574.6
`NC
`8.0
`40.5
`HPN-100
`1133.0
`3.9
`7.2
`83.3
`Sodium PBA
`PAGN
`
`
`
`
`FLO 8.0 48TIPN-100 1098.0
`Cyex = Maximum plasma concentration;
`Tinax = time ofmaximum plasma concentration;
`AUC), = AUC fromtime 0 to 24 hours;
`NC = not calculated
`‘Studydid not include a sodium phenylbutyrate comparator arm, values rep-
`resent HPN-100 dosing only. AUC values represent the AUC frommtime 0 to
`the last measurable plasma concentration.
`
`[0039] One embodimentof 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 amountof 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, if necessary, would be based on the
`observed urinary excretion of PAGN and/or total urinary
`nitrogen (TUN),the difference betweenthe two reflecting 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 urca 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 of factors such as dietary protein and physiological
`stress, as well as the effect of a drug used to promote nitrogen
`excretion.
`
`Oncethe patient’s residual endogenous capacity for
`[0040]
`waste nitrogen excretion has been determined, either as the
`difference between PAGNoutput andtotal nitrogen output or
`as total urinarynitrogen outputin the absence ofan ammonia
`scavenging drug, the tolerable amountofdietary protein can
`be calculated for that patient according to the dosage of the
`ammonia scavenging drug being administered, or the dosage
`ofthe ammonia scavenging drug can be adjusted or calculated
`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
`administeredto a patient withliver disease, including hepatic
`encephalopathy, whereby the starting dose would be based on
`the amount of dictary protein the patient is consuming, the
`anticipated conversion of the drug to PAGN,andthepatient’s
`residual urea synthetic capacity, if any. While the urea syn-
`thetic capacity in patients withliver disease would generally
`be greater than for palients 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
`PAGNandtotal waste nitrogen would adjust for these indi-
`vidual patient characteristics.
`
`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
`1.9
`137.2
`Sodium PBA
`58.8
`3.9
`1.2
`279.8
`IIPN-100
`14.9
`4.0
`NC
`70.9
`Sodium PBA
`63.1
`3.2
`1.7
`395.1
`HPN-100
`30.2
`4.0
`NC
`262.1
`Ilealthy Volunteers and Cirrhotic Patients (100 mg/kg BID)!
`Child-Pugh A
`42.8
`2.3
`1.2
`131.7
`Child-Pugh B
`41.8
`2.9
`3.4
`189.5
`Child-Pugh C
`44.3
`3.1
`1.9
`192.1
`Volunteers
`29.8
`3.0
`2.1
`132.7
`Child-Pugh A
`33.2
`3.8
`1.8
`168.8
`Child-Pugh B
`30.8
`4.5
`2.8
`252.4
`Child-Pugh C
`53.1
`48
`V7
`579.9
`Voluntecrs
`25.5
`3.6
`19
`130.5
`Child-Pugh A.
`37.7
`3.9
`5.0
`335.1
`Child-Pugh B
`38.1
`4.0
`75
`466.99
`Child-Pugh C
`43.1
`5.3
`4.0
`578.4
`Volunteers
`46.3
`43
`72
`55