(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2010/0008859 A1
`SCHARSCHMIDT
`(43) Pub. Date:
`Jan. 14, 2010
`
`US 20100008859A1
`
`(54) METHODS OF TREATMENT USING
`AMMONA-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.:
`1-1.
`(22) Filed:
`
`12/350,111
`
`Jan. 7, 2009
`O
`O
`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.
`30.8
`3. (9%,
`(2006.01)
`A6IPI3/00
`(52) U.S. 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 phenylacetyl
`y
`9.
`ary
`pneny
`y
`glutamine and/or 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 Phenlybutyrate
`
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`Patent Application Publication
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`Jan. 14, 2010 Sheet 1 of 15
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`Figure 1
`
`
`
`Sodium Phenlybutyrate
`
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`Jan. 14, 2010 Sheet 2 of 15
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`US 2010/0008859 A1
`
`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
`PAA to PAGN in the systemic (labeled "central')
`plasma compartment. Bioavailability and drug
`effect is assume to relate directly to plasma
`metabolite Concentations
`
`HPN-100 or
`Buphenyi
`
`--------------
`
`Covariate
`BSAvii.73 x VM1, VM2, VPB, VPA, WPG
`
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`US 2010/0008859 A1
`
`Jan. 14, 2010
`
`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, 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. 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 delivering 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 PAA, and those prodrugs that are metabolized to
`form PBA.
`0004 Hepatic encephalopathy refers to a spectrum of 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 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),
`
`0008 argininosuccinate synthetase (ASS: EC Number
`6.3.4.5; autosomal recessive),
`0009 argininosuccinate lyase (ASL; EC Number 4.3.2.
`1; autosomal recessive),
`0010) arginase (ARG; EC Number 3.5.3.1: autosomal
`recessive), and
`0.011
`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 Ornithine translocase deficiency (hyperomithine
`mia, hyperammonemia, homocitrullinuria or HHH Syn
`drome)
`0.014) Citrin (aspartate glutamate transporter) defi
`ciency
`0015 The common feature of UCD 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
`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 of a patient
`having 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
`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 excess waste nitrogen and
`ammonia by converting it to readily-excreted forms, such as
`phenylacetylglutamine (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. 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 PAA 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
`
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`US 2010/0008859 A1
`
`Jan. 14, 2010
`
`ference Group Consensus Statement from a Conference for
`the Management of Patients with Urea Cycle Disorders,
`Suppl to J Pediatrics, vol. 138(1), S1-S5 (2001)).
`0018 Current treatment guidelines recommend 4 times
`per day dosing, based on the fact that PBA is absorbed rapidly
`from the intestine when administered in the form of sodium
`PBA 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 (HPN-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 of these
`drugs as conventionally assessed based on systemic blood
`levels of the drugs themselves or of the active species pro
`duced in vivo from these drugs does not accurately predict
`removal of waste nitrogen or reduction of 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
`sodiumphenylbutyrate (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(R) (sodium phenylbutyrate), which is the
`sodium salt of PBA along with small amounts of inert ingre
`dients), which is itself a prodrug of phenylacetic acid (PAA),
`are especially subject to the effects described herein.
`
`CONa"
`
`phenylbutyrate
`OH
`
`O
`
`Phenylacetic acid
`O
`NH2
`
`Phenylacetylglutamine
`
`0021 AS used herein 'ammonia Scavenging drugs' is
`defined to include all orally administered drugs in the class
`which contain or are metabolized to phenylacetate. Thus, the
`term includes at least phenylbutyrate, BUPHENYL(R) (so
`dium phenylbutyrate), AMMONAPSR), butyroyloxymethyl
`4-phenylbutyrate, glyceryl tri-4-phenylbutyrate (HPN
`
`100), esters, ethers, and acceptable salts, acids and derivatives
`thereof. These drugs reduce high levels of endogenous
`ammonia by providing phenylacetic acid in vivo, which is
`metabolized efficiently to form phenylacetyl glutamine
`(PAGN). PAGN is efficiently excreted in urine, carrying away
`two equivalents of nitrogen per mole of PAA converted to
`PAGN. References herein to sodium phenylbutyrate are
`understood to include reference to the drug product BUPHE
`NYL(R), and BUPHENYL(R) was used for the Examples herein
`wherever test subjects were treated with sodium phenylbu
`tyrate. Thus the sodium PBA dosages used in the Examples
`generally refer to a dosage of BUPHENYL(R), 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
`that can be converted into PAA within the body. Sodium
`phenylbutyrate (sodium PBA) is one such drug; it is converted
`by oxidative mechanisms into PAA in the body. HPN-100 is
`another such drug: it can behydrolyzed to release PBA, which
`in turn can be oxidized to form PAA. Thus, HPN-100 is a
`prodrug of PBA, and also a prodrug of PAA. Clinical evi
`dence demonstrates that HPN-100 is converted into PAA in
`the body as expected, and that PAA is then linked to a mol
`ecule of glutamine and converted into PAGN, which is elimi
`nated in the urine as predicted. This process can be summa
`rized as follows:
`
`HPN-100-s3PBA-3PAA
`
`PAA+glutamine->PAGN.
`0023 PAGN is mainly excreted in the subject's urine, and
`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 PAA is efficient and fairly
`rapid, but Surprisingly suggest that some conversion of HPN
`to PAGN may occur before the HPN-100 (or PBA, or PAA
`derived from PBA) enters systemic circulation. As a result,
`systemic levels of PAA or PBA are not reliably correlated
`with the efficacy of HPN-100 as an ammonia scavenger.
`0024. In 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 of 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 prodrug is an ester of phenylbutyrate, such as
`those described below; a preferred PBA prodrug for use in the
`invention is HPN-100. These compounds can be made and
`used by methods disclosed in U.S. Pat. No. 5,968,979, which
`is incorporated herein by reference for its description of these
`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
`amount of prodrug will typically refer to the molar amount of
`the active species formed from that prodrug. That active spe
`cies is usually PAA for the prodrugs described herein, and the
`molaramount of a prodrug corresponds to the amount of PAA
`that would form in the body from that amount of the prodrug,
`assuming complete conversion into PAA occurs in vivo.
`
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`US 2010/0008859 A1
`
`Jan. 14, 2010
`
`Thus, for example, a molecule of HPN-100 can be metabo
`lized by ester hydrolysis followed by oxidation to form three
`molecules of PAA, so a mole of HPN-100 would be consid
`ered equimolar to three moles of PAA. Similarly, since HPN
`100 hydrolyzes to form three molecules of PBA (and one
`molecule of glycerin), an equimolar amount of HPN-100
`would be one-third of the molar amount of PBA.
`0026. The following Table sets forth amounts of HPN-100
`that correspond to equimolar amounts of certain relevant
`doses of BUPHENYL(R) (sodium phenylbutyrate). Note that
`the conversion of the dose of sodium PBA to the dose of
`HPN-100 involves correction for their different chemical
`forms i.e. HPN-100 consists of glycerol in ester linkage with
`3 molecules of PBA and contains no sodium; (sodium PBA
`gx0.95=HPN-100g) as well as correction for the specific
`gravity of HPN-100, which is 1.1 g/mL.
`
`the triol backbone liberated by hydrolysis of the 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:
`
`(II)
`
`O
`
`R-0-l R4
`
`0031 wherein R is a C-C alkyl group,
`0032 R is
`
`BUPHENYL (R)
`(sodium PBA)
`450-600 mg/kg/day
`(patients is 20 kg)
`9.9-13.0 g/m2/day
`(patients > 20 kg)
`Maximum Daily
`Dose: 20 g
`
`HPN-100 PBA
`Equivalent
`Dose (mg)
`428-570 mg/kg/day
`
`HPN-100 PBA
`Equivalent
`Dose (mL)
`0.39-0.52 mL/kg/day
`
`94-12.4 g/m2/day
`
`8.6-11.2 mL/m2/day
`
`Maximum Daily
`Dose: 19 g
`
`17.4 mL
`
`0027. The present invention can use prodrugs of the for
`mula (I):
`
`(I)
`
`H
`
`H
`
`H
`
`H
`
`H
`
`O-R
`
`O-R
`
`O-R
`
`0028 wherein R. R. and Rs are independently, H.
`
`(CH2)
`O
`
`O
`
`(C mH2n-2)
`
`0029 and n is Zero or an even number, m is an even
`number and at least one of R, R2, and R is not H. For
`each R, R2, or R, norm is independently selected, so
`the R, R2, and R groups in a compound of formula I do
`not have to be identical. The preferred compounds are
`those wherein none of R, R2, and R is H. and fre
`quently each norm for a particular embodiment is the
`same, i.e., R. R. and R are all the same. The advantage
`over the prior art of decreased dosage is greater with
`Such triesters, and having all three acyl groups the same
`reduces issues related to mixtures of isomers. Moreover,
`
`(CH2)
`
`O
`
`(CnH2n-2)
`
`0033 and n is zero or an even number, and m is an even
`number.
`0034. In Formula II, R can be, for example, ethyl, propyl,
`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 efficient
`beta-Oxidation processes to phenylacetic acid in the body.
`They are thus prodrugs for phenylacetic acid. Where n is 2 or
`4, the esters are also prodrugs for phenylbutyric acid. Prefer
`ably the alkylene oralkenylene carboxylate group contains 24
`or fewer carbon atoms, so n or m is less than 24. In some
`embodiments, n and mare 0, 2, 4 or 6, and in Some preferred
`embodiments in or m is 2.
`0036 Certain preferred embodiments of the invention use
`HPN-100 (Formula III):
`
`(III)
`
`O
`
`O
`
`H
`
`H
`
`H
`
`H
`
`H
`
`O
`
`O
`
`O
`
`O
`
`0037 Total daily dosage of prodrugs like sodium PBA can
`often be selected according to the amount needed to provide
`
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`

`US 2010/0008859 A1
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`
`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 dosage of PAA were known, taking into account the
`fraction of PBA 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 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 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 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 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 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 by the administered nitrogen Scaveng
`ing drug without being influenced by the many other factors
`that can affect plasma ammonia levels.
`
`Plasma Pharmacokinetics of PBA, PAA, and PAGN Comparison across
`Studies
`
`AUC24
`TV2
`Tina
`Cna
`(g himL)
`(h)
`(h)
`(ig/mL)
`Treatment
`Analyte
`Healthy Volunteers (Single Dose - 3 g/m/day PBA Mole Equivalent)
`
`PBA
`
`PAA
`
`PAGN
`
`PBA
`
`PAA
`
`PAGN
`
`Sodium PBA
`221.0
`O.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
`HPN-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
`Healthy Volunteers and Cirrhotic Patients (100 mg/kg BID)"
`Child-Pugh A
`42.8
`2.3
`1.2
`131.7
`Child-Pugh B
`4.1.8
`2.9
`3.4
`1895
`Child-Pugh C
`44.3
`3.1
`1.9
`1921
`Volunteers
`29.8
`3.0
`2.1
`132.7
`Child-Pugh A
`33.2
`3.8
`1.8
`1688
`Child-Pugh B
`30.8
`4.5
`2.8
`2S2.4
`Child-Pugh C
`53.1
`4.8
`7.7
`579.9
`Volunteers
`25.5
`3.6
`1.9
`13 O.S
`Child-Pugh A
`37.7
`3.9
`S.O
`335.1
`Child-Pugh B
`38.1
`4.0
`7.5
`466.99
`Child-Pugh C
`43.1
`5.3
`4.0
`578.4
`Volunteers
`46.3
`4.3
`7.2
`550.9
`UCD Subjects (Multiple Dose - PBA Mole Equivalent)
`
`PBA
`
`Sodium PBA
`HPN-100
`
`1410
`70.1
`
`2.1
`6.1
`
`NC
`NC
`
`739.0
`S4O.O
`
`-continued
`
`Plasma Pharmacokinetics of PBA, PAA, and PAGN Comparison across
`Studies
`
`Analyte
`
`Treatment
`
`PAA
`
`PAGN
`
`Sodium PBA
`HPN-100
`Sodium PBA
`HPN-100
`
`Coax.
`(Lig/mL)
`
`Ta
`(h)
`
`53.0
`4O.S
`83.3
`71.9
`
`8.1
`8.O
`7.2
`8.O
`
`TV2
`(h)
`
`NC
`NC
`3.9
`4.8
`
`AUC24
`(g himL)
`
`595.6
`S74.6
`1133.0
`1098.0
`
`C = maximum plasma concentration;
`T = time of maximum plasma concentration;
`AUC = AUC from time 0 to 24 hours;
`NC = not calculated
`'Study did not include a sodium phenylbutyrate comparator arm, values rep
`resent HPN-100 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 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 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 of an 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
`of the 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
`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.
`
`Page 20 of 39
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`
`0042 Another embodiment is a method for determining or
`adjusting allowable dietary protein in the diet of a patient with
`UCD or with hepatic encephalopathy, who is being treated
`with an oral PAA-forming ammonia Scavenging drug,
`whereby the amount of allowable protein would be deter
`mined by the amount of PAGN 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
`used to adjust dietary protein intake while administering a
`fixed dosage of an ammonia Scavenging drug, or the dosage of
`the ammonia Scavenging drug can be determined according to
`the amount needed to facilitate elimination of the waste nitro
`gen from 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 PAA-forming
`ammonia Scavenging drug being administered. When making
`these calculations or adjustments, it is Suitable to assume that
`about 47% 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 support body growth), and that about 16% of
`protein, on average, is nitrogen (see Brusilow 1991).
`0043. It has generally been assumed for such determina
`tions that a prodrug would be converted with 100% efficiency
`into PAGN for elimination see, e.g., Berry et al., J. Pediatrics
`138(1), S56-S61 (2001) where FIG. 1 assumes 100% conver
`sion;andone report found that about 80-90% of PAA or PBA
`was excreted from a specific individual as PAGN. Brusilow,
`Pediatric Research 29(2), 147-150 (1991). It has now been
`found that HPN-100 and phenylbutyrate are both converted
`into urinary PAGN at an overall efficiency of about 60% to
`about 75% on average (about 60% conversion efficiency was
`seen in UCD patients and about 75% conversion was seen in
`cirrhotic patients, for example); consequently, this efficiency
`factor can be used to more accurately calculate or determine
`initial dosing levels for these drugs, or dietary protein levels
`acceptable for patients who use these drugs. Given this con
`version rate, each gram of HPN-100 can facilitate elimination
`of waste nitrogen from about a gram (~1.3 grams) of dietary
`protein per day. Note that PAGN carries away two molecules
`of ammonia per molecule of PAGN. Examples of calculations
`based on these parameters are provided in Examples 9 and 10
`herein.
`0044. In one aspect, the invention provides a method for
`transitioning a patient from phenylacetate or phenylbutyrate
`to HPN-100 or other esters or prodrugs of phenylbutyrate.
`The method involves administering an initial dosage of the
`prodrug that is selected based on the patient’s current dosage
`of phenylacetate orphenylbutyrate, and is adjusted according
`to the levels of excreted PAGN that result when the prodrug is
`administered.
`0045. In some embodiments, the transition from phenyl
`butyrate might be undertaken in more than a single step and
`urinary excretion of PAGN and total nitrogen would allow
`monitoring of ammonia Scavenging during the transition (e.g.
`for clinically fragile patients with a propensity for frequent
`hyperammonemia). The methods can use two, three, four,
`five, or more than five steps as judged clinically prudent. At
`each step, a fraction of the initial dosage of phenylbutyrate
`corresponding to the number of steps used for the transition is
`
`replaced by an appropriate, amount (i.e. the amount necessary
`to deliver an equimolar amount of PBA) of HPN-100 or other
`prodrug of phenylbutyrate, e.g., if the transition is to be done
`in three steps, about one-third of the phenylbuty