US 20100008859Al
`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2010/0008859 A1
`SCHARSCHMIDT
`(43) Pub. Date: Jan. 14, 2010
`
`
`(54)
`
`(76)
`
`METIIODS OF TREATMENT USING
`AlVlMONIA-SCAVENGING DRUGS
`
`Inventor:
`
`Bruce SCHARSCHNIIDT, 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 US. Application Data
`
`(60)
`
`Provisional application No. 61/093,234, filed 011 Aug.
`29, 2008, provisional application No. 61/048,830,
`filed on Apr. 29, 2008.
`
`Publication Classification
`
`(51‘)
`
`Int. Cl.
`(2006.01)
`A61K 49/00
`(2006.01)
`A61K 31/192
`(2006.01)
`A61P 13/00
`(52) us. Cl. ........................................ .. 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 phenylaeetyl-
`glutamine and/0r total urinary nitrogen. The invention pro-
`vides methods to select an appropriate dosage of a PBA
`prodrug based on the patient’s dietary protein intake, or based
`on previous treatments administered to the patient. The meth—
`ods are applicable to selecting or modifying a dosing regimen
`for a subject receiving an orally administered ammonia scav-
`enging drug.
`
`Sodium Phcnlybmyrate-
`J,
`.
`NW.
`
`
`
`
`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
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`

`

`Patent Application Publication
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`Jan. 14, 2010 Sheet 1 0f 15
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`US 2010/0008859 Al
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`Figure 1
`
`Sodium Phenlybutyrate-
`
`
`
`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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`Patent Application Publication
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`Jan. 14, 2010 Sheet 2 0f 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:
`,
`This model only allows for conversion of PBA to
`PM to PAGN in the systemic (labeled ‘centra|’)
`
`plasma compartment. Bioavailability and drug
`effect is assume to relate directly to plasma
`metabolite concentations
`
`
`
`. HPN-100 or
`BuPhe"VI®
`
`,................ _,
`:
`'
`
` Covariate
`
`BSA/1.73 x VMI, VM2, VPBl VPA, VPG
`
`
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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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`Patent Application Publication
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`Jan. 14, 2010 Sheet 3 0f 15
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`Par Pharmaceutical, Inc. Ex. 1004
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`Patent Application Publication
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`Jan. 14, 2010 Sheet 4 0f 15
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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
`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
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
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`Patent Application Publication
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`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 9 of 39
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`Patent Application Publication
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`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
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`Patent Application Publication
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`Jan. 14, 2010 Sheet 10 0f 15
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`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
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`Patent Application Publication
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`Jan. 14, 2010 Sheet 11 0f 15
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`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
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`Patent Application Publication
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`Jan. 14, 2010 Sheet 12 0f 15
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`US 2010/0008859 Al
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`Patent Application Publication
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`Patent Application Publication
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`Jan. 14, 2010 Sheet 14 0f 15
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`US 2010/0008859 Al
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`Patent Application Publication
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`Jan. 14, 2010 Sheet 15 0f 15
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`US 2010/0008859 A1
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`Jan. 14, 2010
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`METHODS OF TREATMENT USING
`ANIMON lA-SCAVE VGlNG DRUGS
`
`CROSS—REFERENCE TO RELATED
`APPLICATIONS
`
`
`
`[0001] This application claims benefit of priority to US.
`Provisional application Ser. No. 61/093,234, filed Aug. 29,
`2008, which is incorporated herein by reference in its entirety.
`This application is also related to the US. 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 from the body. The compounds can be
`orally administered small-molecule drugs, and the invention
`provides methods for deliverng these compounds and select-
`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 from it 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 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 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, i.e.,
`prodrugs of FAA, and those prodrugs that are metabolized to
`form PEA.
`[0004] Hepatic encephalopathy refers to a spectrum ofneu-
`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
`FIG. 1, which also illustrates how certain ammonia—scaveng—
`ing drugs act to assist in elimination of excessive ammonia.
`The enzymes including their Enzyme Commission (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 transcarbamylase (OTC; EC Number
`2.1.3.3; X—linked),
`
`
`
`defi—
`
`argininosuccmate synthetase (ASS; EC Ntunber
`[0008]
`6.3.4.5; autosomal recessive).
`
`[0009]
`argininosuccinate lyase (ASL; EC Number 4.3.2.
`1; autosomal recessive),
`[0010]
`arginase (ARC; EC Number 3.5.3.1; autosomal
`recessive), and
`
`[0011] N—acetyl glutamine synthetase (NAGS 1; EC
`Number 2.3.1.1; autosomal recessive)
`[0012] Mitochondrial transporter deficiency states Which
`mimic many features of urea cycle enzyme deficiencies
`include the following:
`[0013] Omithine translocase deficiency (hyperomithine-
`mia, hyperammonemia, homocitrullinuria or III III Syn-
`drome)
`[0014] Citrin (aspartate glutamate transporter)
`ciency
`[0015] The common feature 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
`JCD or HE, the body‘s intrinsic capacity for waste nitrogen
`excretion is less than the body’s waste nitrogen production
`tased on a normal diet that contains significant amounts of
`orotein. As a result, nitrogen builds up in the body of a patient
`laving a nitrogen retention disorder, and usually results in
`excess ammonia in the blood. This has various toxic effects;
`drugs that help eliminate the excess ammonia are an impor-
`ant part of an overall management strategy for such disor—
`ders.
`To avoid build-up of ammonia to toxic levels in
`[0016]
`oatients with nitrogen retention states, dietary intake of pro—
`ein (a primary source of exogenous waste nitrogen) must be
`aalanecdby the patient’s ability to eliminate cxecss 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 (hyperamrnonemia). 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 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
`(e.g. 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
`phenylbutyrate was reportedly excreted in the urine as PAGN,
`current treatment guidelines typically either assume complete
`conversion of sodium phenylbutyrate or other FAA prodrugs
`to PAGN (e.g. Berry et al., J. Pediatrics, vol. 138, S56-S61
`(2001)) or do not comment on the implications of incomplete
`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 A1
`
`Jan. 14, 2010
`
`ference Group ‘Consensus Statementfi’am a Conferencefor
`the [Management of Patients with Urea Cycle Disarders’,
`Suppl lo JPedialrics, vol. 138(1), 81-35 (2001)).
`[0018] Current treatment guidelines recommend 4 times
`per day do sing, based on the fact that FBA is absorbed rapidly
`from the intestine when administered in the form of sodium
`FBA and 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
`grams 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—
`butyrate and glyceryl
`tri—[4—phenylbutyrate]
`(HFN—100),
`based upon the urinary excretion of the drug metabolite phe—
`nylacetylglutamine (PAGN) and/or total urinary nitrogen. It
`is based in part on the discoveries that bioavailability ofthese
`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
`removal ofwaste 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 (NaFBA, or sodium FBA) to FAGN to
`urinary PAGN is incomplete, typically about 60-75%. Fro-
`drugs of phenylbutyrate (FBA,
`the active ingredient
`in
`BUPHENYL® (sodium phenylbutyrate), which is
`the
`sodium salt of FBA along with small amounts ofinert ingre-
`dients), which is itself a prodrug of phenylacetic acid (FAA),
`are especially subject to the effects described herein.
`
`COZ'Nafr
`
`plieny lbthyrate
`()II
`
`0
`
`Phenylacetic acid
`NH2
`
`0
`
`1,,1,]
`
`H
`
`O
`
`Phenylacet'ylglutam inc
`
`[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), AMMONAFS®, butyroyloxymethyl—
`4—phenylbutyrate, glyceryl
`tri—[4—phenylbutyrate]
`(HFN—
`
`
`
`100‘), esters, ethers, and acceptable salts, acids and derivatives
`hereof. These drugs reduce high levels of endogenous
`ammonia by providing phenylacetic acid in vivo, which is
`metabolized efficiently to form phenylacetyl glutamine
`(PAGN). PAGN is efficiently excreted in urine, carrying away
`wo equivalents of nitrogen per mole of PAA converted to
`)AGN. References herein to sodium phenylbutyrate are
`understood to include reference to the drug product BUFHE—
`
`\IYL®, and BUPHENYL® was used for the Examples herein
`wherever test subjects were treated with sodium phenylbu—
`yrate. Thus the sodium FBA dosages used in the Examples
`
`generally refer to a dosage of BUPHENYL®, and the
`amounts of sodium phenylbutyrate in those Examples should
`3e interpreted accordingly. Note that the terms ‘ammonia
`scavenger” and ‘nitrogen scavenger” are used interchangeably
`in this invention, reflecting the fact that the drugs described
`rerein lower blood ammonia through elimination of waste
`nitrogen in the form of FAGN .
`[0022]
`In some embodiments, the invention uses prodrugs
`hat can be converted into FAA within the body. Sodium
`ahenylbutyrate (sodium FBA) is one such drug; it is converted
`3y oxidative mechanisms into FAA in the body. IIFN- 100 is
`another such drug: it can be hydrolyzed to release FBA, which
`in turn can be oxidized to form PAA. Thus, HFN-100 is a
`arodrug of FBA, and also a prodrug of PAA. Clinical evi-
`dence demonstrates that HFN-100 is converted into FAA in
`he body as expected, and that FAA is then linked to a mol—
`ecule of glutamine and converted into FAGN, which is elimi—
`nated in the urine as predicted. This process can be summa—
`rized as follows:
`HFN-100+3FBA63 FAA
`
`FAA+glummmc4>FAGN
`
`FAGN is mainly excreted in the subject’s urine, and
`[0023]
`removes two molecules of ammonia per molecule of excreted
`FAGN. Each HFN—100 molecule forms three FAA molecules,
`so each molecule of HFN—100 can promote excretion of six
`molecules of ammonia. The clinical results suggest that con—
`version of HFN—100 into FBA and FAA is eflicient and fairly
`rapid, bth surprisingly suggest that some conversion of HFN
`to PAGN may occur before the HFN-100 (or FBA, or FAA
`derived from FBA) enters systemic circulation. As a result.
`systemic levels of FAA or FBA are not reliably correlated
`with the efficacy of HFN -100 as an ammonia scavenger.
`[0024]
`In some embodiments, the invention uses a prodrug
`of FBA, including HFN-100 and other esters of phenylbu-
`tyrate. The FBA prodrug is thus a prodrug ofa prodrug, since
`FBA acts to scavenge ammonia after it is converted to FAA
`and is thus considered a prodrug of FAA. In some embodi-
`ments, the FBA prodrug is an ester ofphenylbutyrate, such as
`those described below; a preferred FBA prodrug for use in the
`invention is IIFN-IOO. These compounds can be made and
`used by methods disclosed in US. Fat. 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. W'here one of the drugs is a prodrug, the
`amount ofprodrug will typically refer to the molar amount of
`the active species formed from that prodrug. That active spe—
`cies is usually FAA for the prodrugs described herein, and the
`molar amount ofa prodrug corresponds to the amount ofFAA
`that would form in the body from that amount ofthe prodrug,
`assuming complete conversion into FAA 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 A1
`
`Jan. 14, 2010
`
`D.)
`
`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 IlPN-lOO 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—l 00
`would be one-third ofthe molar amount of PBA.
`[0026] The following Table sets forth amounts ofHPN—lOO
`that correspond to equirnolar amounts of certain relevant
`doses of BUPHENYL® (sodium phenylbutyrate). Note that
`the conversion of the dose of sodium PBA to the dose of
`HPN-lOO involves correction for their different chemical
`forms [i.e. HPN-l 00 consists of glycerol in ester linkage with
`3 molecules of PEA and contains no sodium; (sodium PBA
`[g]><0.95:HPN-100 [g] )] as well as correction for the specific
`gravity of HPN-lOO, which is 1.1
`
`BUPHENYL ®
`[sodium PEA)
`450-600 nigkg/day
`(patienm :’ 20 kg)
`93713.0 g/mE/day
`(patients > 20 kg)
`Maximum Daily
`Dose: 20 g
`
`HPN-l 00 PBA
`Equivalent
`Dose (mg)
`428-570 nigkg/day
`
`HPN- 100 PBA
`Equivalent
`Dose (ml,)
`0.39-0.52 n1L/kg/day
`
`9.47114 g/mE/day
`
`8.67112 mL/mZ/day
`
`Maximum Daily
`Dose: 19 g
`
`17.4 mL
`
`[0027]
`mula (l):
`
`The present invention can use prodrugs of the for-
`
`(I)
`
`[0028]
`
`wherein R1, R2, and R3 are independently, H,
`
`flifl2m
`g
`0‘ :(CmHZm-Z)
`
`or
`
`and n is zero or an even number, in is an even
`[0029]
`number and at least one of R1, R2, and R3 is not H. For
`each R1, R2, or R3, 11 or m is independently selected, so
`the R1, R2, and R3 groups in a compound of formula I do
`not have to be identical. The preferred compounds are
`those wherein none of R1, R2, and R3 is H, and fre—
`quently each n or m for a particular embodiment is the
`same, i.e,, RI , R2, and R3 are all the same. The advantage
`over the prior art of decreased dosage is greater with
`such triesters, and having all three acyl groups the same
`reduces issues related to mixtures of isomers. Moreover,
`
`the triol backbone liberated by hydrolysis ofthe esters is
`glycerol, a normal constituent of dietary triglyceride
`which is non-toxic.
`[0030] The present invention also utilizes phenylbutyrate
`and phenylaeetate prodru gs of the formula II:
`
`0
`Hr R4
`
`(ll)
`
`[0031] wherein R is a Cl-Clo alkyl group,
`[0032] R4 is
`
`2m
`
`01'
`
`(CmHzm..7}‘ :
`
`and n is zero or an even number, and in is an even
`
`[0033]
`number.
`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 alkanoie acid
`portion, which include phenylaeetie acid esters and those of
`phenylbutyric acid, etc, which can be converted by efficient
`beta-oxidation processes to phenylacetie acid in the body.
`They are thus prodrugs for phenylaeetic 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 11 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.
`[003 6] Certain preferred embodiments ofthe invention use
`llPN— l 00 (Formula 111):
`
`(in)
`
`O
`
`H
`H
`
`H
`
`H
`
`H
`
`O
`
`O
`O
`
`0
`
`O
`
`[0037] Total daily dosage ofprodrugs like sodium PBA can
`often be selected according to the amount needed to 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 A1
`
`Jan. 14, 2010
`
`an appropriate amount of the active species, if that amount is
`known or can be determined. PBA is a prodrug for PAA;
`therefore, an initial dose of PBA could be selected if an
`effective do sage of PAA were known, taking into account the
`fraction ofPBA that is converted into FAA and ultimately into
`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 and the dose ofthe 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 prodrug administered
`or with ammonia elimination; forinonitoring 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 and/or PAA blood levels) are provided herein.
`[0038] The following 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 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 by the administered nitrogen scaveng-
`ing drug without being influenced by the many other factors
`that can affect plasma ammonia levels.
`
`l’lasma l’harmacokinctics ofl’BA, FAA, and PAGN Comparison across
`Studies
`
`Analyte
`
`Treatment
`
`Cm
`(iig'mL)
`
`1%
`(ll)
`
`W2
`(l1)
`
`AUC24
`(pg - ll/mL)
`
`—continued
`
`Plasma Pharmacokinetics of PBA, FAA, and PAGN Comparison across
`Studies
`
`Analytc
`PAA
`
`AUC24
`Tl/l
`Tmax
`CW”
`tug ' h/mL)
`(h)
`(h)
`(rig/ml.)
`Treatment
`595.6
`NC
`8.1
`53.0
`Sodium PBA
`574.6
`NC
`8.0
`40.5
`HPN—lOO
`1133.0
`3.9
`7.2
`83.3
`Sodium PBA
`PAGN
`
`
`
`
`71.9 8.0 4.8IlPN—100 1098.0
`CW“ = maximum plasma concentration:
`T"m = time ofmaximum plasma concentration;
`AUC“ = AUC from time 0 to 24 hours;
`NC = not calculated
`1Study did not include a sodium phenylbutyrate comparator arm, values rep-
`resent HPN-lOO dosing only. AUC values represent the AUC from time 0 to
`the last measurable plasma 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 amount of dietary protein the patient is eonsuin—
`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 between the 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 sometimes as 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 of factors such as dietary protein and physiological
`stress, as well as the effect 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
`difference between PAGN output and total nitrogen output or
`as total urinary nitrogen output in the absence ofan ammonia
`scavenging drug, the tolerable amount of dietary 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 canbe adjusted or calculated
`to compensate for an estimated protein intake.
`[0041] Another embodiment is a method for 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
`the amount of dietary protein the patient is consuming, the
`anticipated conversion of 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.
`
`Healthy Volunteers (Single Dose - 3 g/mZ/day PBA Mole Equivalent)
`PBA
`Sodium P ]A
`221.0
`0.9
`0.7
`542.6
`I» N- 00
`37.0
`2.4
`1.9
`137.2
`Sodium P 3A
`58.8
`3.9
`1.2
`279.8
`I N- 00
`14.9
`4.0
`NC
`70.9
`Sodium P 3A
`63.1
`3.2
`1.7
`395.1
`I» N- 00
`30.2
`4.0
`NC
`262.1
`Healt 1y Volunteers and Cirrhotic Patients (100 mg/kg BID)l
`C ild- ug A
`42.8
`2.3
`1.2
`131.7
`C ild- ug B
`41.8
`2.9
`3.4
`189.5
`Ciild- ugiC
`44.3
`3.1
`1.9
`192.1
`Volunteers
`29.8
`3.0
`2.1
`132.7
`C ild- ug A
`33.2
`3.8
`1.8
`168.8
`Ciild- ugiB
`30.8
`4.5
`2.8
`252.4
`C ild- ug C
`53.1
`4.8
`7.7
`579.9
`Volunteers
`25.5
`3.6
`1.9
`130.5
`Ciild- ugiA
`37.7
`3.9
`5.0
`335.1
`C ild- ug B
`38.1
`4.0
`7.5
`466.99
`C ild- ug C
`43.1
`5.3
`4.0
`578.4
`Volimteeis
`46.3
`4.3
`7.2
`550.9
`UCD Subjects (Multiple Dose - PBA Mole Equivalent)
`Sodium P 3A
`141.0
`2.1
`NC
`H N- 00
`70.1
`6.1
`NC
`
`FAA
`
`PAGN
`
`PBA
`
`PAA
`
`PAGN
`
`PBA
`
`
`
`
`
`739.0
`540.0
`
`Par Pharmaceutical , Inc. Ex. 1004
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 20 of 39
`
`

`

`US 2010/0008859 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—forming ammonia scavenging drug,
`whereby the amount of allowable protein would be deter—
`mined by the amount of PAGN 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 pro