`
`pharmacology review
`
`odium Phenvlacetat
`mand
`oa1um Ben4o.ate
`1n e
`at Nepnata
`eatment
`PHARMACOLOGY
`EW
`
`of acute hyperammooemia and asso­
`
`Anna-Kaisa Niemi, MO, PhD." Gregory
`
`
`
`ciated encephalopathy in patients
`M. Enns, MB, ChB·
`who have urea cycle disorders
`
`(UCDs). Its concomitant use with
`Introduction
`
`
`
`protein restriction, provision of �de­
`
`Ammonia is present in all body fluids
`
`
`quate calorics to prevent catabohsm,
`Author Disclosure
`
`
`
`and exists primarily as ammonium
`
`
`arginine hydrochloride, and hemodi­
`
`Or Niemi did not disclose any
`
`ion at physiologic pH. Hyperam­
`
`
`alysis in treating neonatal hyperam­
`
`
`
`financial relationships relevant to
`
`monemia is defined as a blood am­
`
`mooernia helps prevent the reaccu­
`
`
`monia concentration greater than
`
`
`this article. Dr Enns disclosed that he
`
`mulation of ammonia by increasing
`
`about 100 mcmol/L in neonates or
`
`
`has received honoraria for lectures
`
`
`waste nitrogen excretion. The pur­
`
`50 mcmol/L in children and adults
`
`pose of this article is to review the
`
`and consultant work from Ucyclyd
`
`
`
`(precise cut-offs vary, depending on
`
`pharmacology and use of NAPA/
`
`Pharma, Inc.
`
`
`individual laboratory normative
`
`NABZ in the treatment of neonatal
`
`
`ranges). The concentration of am­
`hyperammonemia.
`monia is 10 times higher in tissue
`
`than in blood. A 5-to 10-fold in­
`Neonatal Hyperammonemia.
`
`
`
`
`Because the inheritance of most 10-
`
`crease in blood ammonia concentra­
`
`
`bom errors of metabolism that cause
`
`tion usually is toxic to the nervous
`
`
`neonatal hyperammonemia is auto­
`system.
`
`somal recessive ( exceptions include
`Hyperammonemia in the neonatal
`
`period, especially when due to inborn
`
`
`ornithioe cranscarbamylase [OTC)
`
`
`deficiency, which is X -linked, and
`
`
`errors of metabolism, can progress rap­
`hyperinsulioism/hyperammonernia
`
`idly and cause severe oeurologic dam­
`
`syndrome, which is autosomal dom­
`
`age or early death. Hyperammonemia
`
`inant), family history may offer no
`
`can be caused by inborn e!IOrs of me­
`
`
`tabolism as well as by a variety of ac­
`
`information of note or may reveal
`
`
`unexplained neonatal deaths.
`
`
`quired conditions (fables 1 and 2).
`UCDs are the most common
`
`
`Urgent treatment is required because
`
`cause of neonatal hyperammonemia
`
`
`of the potential for irreversible neuro­
`Abbreviations
`
`and typically present with symptoms
`
`logic sequelae that can, in many cases,
`
`AL. argininosuccinic acid lyase
`
`
`be prevented by prompt diagnosis and
`
`
`of poor feeding, lethargy, hypotooia,
`
`
`
`irritability, seizures, respiratory dis­
`
`ASA: argininosuccinic acid
`
`institution of therapy.
`
`ATP: adenosine triphosphate
`
`
`tress, grunting, and hyperventilation.
`
`Thecombinationofsodiumphenyl­
`
`
`Patients may have a bulging fonta­
`BZ: benroate
`
`acetate (NAPA) and sodium benzo­
`
`
`nelle if intracraoial pressure is in­
`CoA: coenzyme A
`
`ate (NABZ) in a 10%/10% solution is
`
`an intravenously administered United
`HIP: hippurate
`
`
`
`creased. Because the clinical presen­
`NABZ: sodium bcnzoatc
`
`tation of hyperammonernia is
`
`States Food and Drug Administra­
`NAPA: sodium phcnylacctate
`
`
`nonspecific, other disorders common
`
`tion (FDA)-approved drug used as
`
`OTC: ornithine transcarbamylase
`
`
`in neonates, such as sepsis, cardiac
`
`
`adjunctive therapy for the treatment
`
`PA: phenylacetic acid
`
`
`failure, and intracranial hemorrhage,
`PAGN: phenylacetylglutaminc
`
`
`are included in the differential diag­
`
`PD: peritoneal dialysis
`
`nosis. Therefore, blood ammonia
`1ltpartm•nt of Pediatrics. Division of Medical
`
`
`
`
`Genetics, Stanfo,d University School of Medicine,
`UCO: urea cycle disorder
`
`concentrations should be measured
`
`Stirnfonl, Calif.
`
`Page 1 of 10
`
`Horizon Exhibit 2022
`Lupin v. Horizon
`IPR2017-01159
`
`

`

`Table 1. Inborn Errors of Metabolism
`Associated With Hyperammonemia
`Urea cycle defects
`● N-acetylglutamate synthetase deficiency
`● Carbamyl phosphate synthetase deficiency
`● Ornithine transcarbamylase deficiency
`● Argininosuccinate synthetase deficiency (citrullinemia)
`● Argininosuccinate lyase deficiency
`● Arginase deficiency
`Amino acid transporter deficiencies
`● Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome
`● Lysinuric protein intolerance
`● Citrin deficiency (citrullinemia type II)
`Organic acidemias
`● Methylmalonic acidemia
`● Propionic acidemia
`● Isovaleric acidemia
`● Multiple carboxylase deficiency
`● Multiple acyl-CoA dehydrogenase deficiency
`● 3-Hydroxymethylglutaryl-CoA dehydrogenase deficiency
`● 3-Methylcrotonyl-CoA carboxylase deficiency
`● 3-Oxothiolase deficiency
`● L-2-Hydroxyglutaric acidemia
`● 3-Methylglutaconyl-CoA hydratase deficiency
`Fatty acid oxidation defects
`● Carnitine transporter deficiency
`● Carnitine palmitoyl transferase 2 deficiency
`● Carnitine-acylcarnitine translocase deficiency
`● Medium-chain acyl-CoA dehydrogenase deficiency
`● Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency
`● Very-long-chain acyl-CoA dehydrogenase deficiency
`Pyruvate carboxylase deficiency
`Mitochondrial disorders
`Hyperinsulinism/hyperammonemia syndrome (glutamate dehydrogenase
`mutations)
`Delta1-pyrroline-5-carboxylate synthase deficiency
`
`in all neonates presenting with non-
`specific symptoms of distress. If the
`concentration is elevated, diagnostic
`evaluations and treatment should be
`started immediately (Tables 3 and 4).
`
`Early Efforts in
`Hyperammonemia Therapy
`A number of different
`therapies
`aimed at removing accumulated am-
`monia in cases of hyperammonemic
`encephalopathy
`have
`been
`at-
`tempted, including administration of
`lactulose (reduces the production or
`
`absorption of the end products of
`bacterial nitrogen metabolism in the
`colon), (1) exchange transfusion,
`(2)(3)(4) peritoneal dialysis, (3)(4)
`hemodialysis, (3)(4)(5) and supple-
`mentation with nitrogen-free ana-
`logues of essential amino acids. (6)
`(7)(8) Although children treated
`with alpha-keto amino acid ana-
`logues
`showed some clinical
`im-
`provement, such as improved seizure
`control, attention span, and weight
`gain, death in infancy remained com-
`mon. (6)(7)(8) Exchange transfu-
`
`pharmacology review
`
`sions are ineffective in managing
`hyperammonemia. In 15 patients
`treated by exchange transfusion, the
`decrease in ammonia values immedi-
`ately following the procedure was
`not statistically significant. (9) Peri-
`toneal dialysis (PD) has shown vari-
`able efficacy in treating hyperam-
`monemia. Seven neonates who had
`UCDs showed a significant decrease
`in plasma ammonia values (85%⫾6%,
`P⬍0.001) following PD for a mean
`duration of 60 hours, but PD was
`ineffective in 13 older children. (9)
`The early use of these treatments pro-
`longed survival
`in some cases, but
`overall efficacy was disappointing, and
`the mortality and morbidity associated
`with UCDs continued to be high.
`
`Table 2. Causes of
`Acquired
`Hyperammonemia
`Sampling artifact
`
`Cardiovascular
`● Patent ductus venosus
`● Portocaval shunt
`● Hypovolemia
`● Congestive heart failure
`Perinatal asphyxia
`
`Liver failure
`● Infectious hepatitis (eg, herpes
`simplex virus)
`Bacterial colonization
`(urease-positive organisms)
`● Neurogenic bladder
`● Prune belly syndrome
`● Blind loop syndrome
`● Ureterosigmoidostomy
`Iatrogenic
`● Valproate
`● Arginine deficiency
`● Total parenteral nutrition
`
`NeoReviews Vol.7 No.9 September 2006 e487
`
`Page 2 of 10
`
`

`

`pharmacology review
`
`<24 h or>24 h after birth
`
`>24 h after birth
`
`2. Organic acidemias (eg, MMA, PA, IVA),
`defects of fatty acid oxidation,
`congenital lactic acidosis
`3. Urea cycle defects:
`a) CPS deficiency
`
`Table 3. Differential Diagnosis of Neonatal Hyperammonemia
`Onset
`Cause
`Clues to Diagnosis
`<24 h after birth
`1. THAN
`● Preterm infant
`● No acidosis/ketosis
`● Term infant
`● Acidosis (ⴙ/ⴚ 1 lactate)
`● ⴙ/ⴚ ketosis
`No acidosis, sometimes alkalosis
`● Low/absent citrulline
`● Urine orotic acid low
`● Low/absent citrulline
`● Urine orotic acid markedly elevated
`● Citrulline markedly elevated
`(>1,000 mcmol)
`● No ASA in urine
`● Urine orotic acid elevated
`● Citrulline moderately elevated
`(100 to 300 mcmol)
`● ASA present in urine
`● Urine orotic acid elevated
`
`b) OTC deficiency
`
`c) AS deficiency
`
`d) AL deficiency
`
`Fatty acid oxidation disorders, especially carnitine-acylcarnitine translocase deficiency, and organic acidemias may be difficult to distinguish from urea cycle
`defects in some instances. Metabolic acidosis, relatively high blood urea nitrogen (BUN) (urea cycle defects tend to be associated with a low BUN), and ketosis
`are more typical of organic acidemias. Hypoketotic hypoglycemia is suggestive of a fatty acid oxidation defect, but the level of ketosis is not always a reliable
`indicator in neonates. Prominent lactic acidosis may suggest pyruvate carboxylase deficiency or mitochondrial disorders. AL⫽argininosuccinate lysase,
`AS⫽argininosuccinate synthetase, ASA⫽argininosuccinic acid, CPS⫽carbamyl phosphate synthetase, IVA⫽isovaleric acidemia, MMA⫽methylmalonic
`acidemia, OTC⫽ornithine transcarbamylase; PA⫽propionic acidemia, THAN⫽transient hyperammonemia of the newborn
`
`Alternative Pathway Therapy
`In 1914, Lewis demonstrated that
`NABZ could divert urea nitrogen to
`hippurate (HIP) nitrogen in two
`healthy subjects. (10) After ingestion
`of single 6- or 10-g aliquots of
`NABZ, blood urea nitrogen and am-
`monia levels fell, and urine HIP ex-
`cretion showed a prominent rise,
`with little change in total urine nitro-
`gen excretion. Shiple and Sherwin
`(11) later showed that oral adminis-
`tration of phenylacetic acid (PA) re-
`sults in substitution of phenylacetyl-
`glutamine (PAGN) nitrogen for urea
`nitrogen in urine. Furthermore, co-
`administration of benzoate (BZ) and
`PA resulted in as much as 60% of
`urine nitrogen being excreted as HIP
`and PAGN. (11) Subsequently, the
`enzymes responsible for these reac-
`tions
`(acyl-CoA:glycine and acyl-
`CoA:glutamine N-acyltransferases)
`were identified and localized to both
`
`e488 NeoReviews Vol.7 No.9 September 2006
`
`the kidney and liver in humans and
`primates. (12)(13)(14)(15) Synthe-
`sis of HIP (from conjugation of gly-
`cine with BZ) and PAGN (from con-
`jugation of glutamine with PA)
`requires
`adenosine
`triphosphate
`(ATP) and coenzyme A (CoA). (16)
`In 1979, Brusilow and associates
`(17) suggested that the use of en-
`dogenous biosynthetic pathways of
`non-urea waste nitrogen excretion
`could substitute for defective urea syn-
`thesis in patients who have UCDs. By
`promoting the synthesis of non-
`urea nitrogen-containing metabo-
`lites whose excretion rates are high or
`may be augmented, theoretically total
`body nitrogen load could be decreased
`despite the absence of normal urea cy-
`cle function. Two classes of such me-
`tabolites are: 1) urea cycle intermedi-
`ates (citrulline and argininosuccinic
`acid) and 2) amino acid acylation
`products (HIP and PAGN). (18)
`
`Urea Cycle Intermediates
`In argininosuccinic acid lyase (AL)
`deficiency,
`argininosuccinic
`acid
`(ASA) accumulates and is excreted in
`the urine. Because ASA contains two
`waste nitrogen atoms, production of
`this metabolite can be exploited to
`excrete waste nitrogen in AL defi-
`ciency, provided that an adequate
`amount of ornithine is present to
`supply the necessary carbon skele-
`tons for ASA biosynthesis. (19) By
`administering pharmacologic doses
`of arginine, ornithine is synthesized
`by the action of arginase. Citrulline
`and ASA subsequently are produced
`by the sequential action of OTC and
`argininosuccinic acid synthetase. In
`AL deficiency, ASA cannot be me-
`tabolized further and is excreted in
`the urine, along with waste nitrogen
`(Fig. 1). (17)(18)(19)
`Similarly, citrulline can serve as a
`
`Page 3 of 10
`
`

`

`Table 4. Management of Neonatal
`Hyperammonemia Caused by Urea Cycle
`Defects
`Laboratory studies
`● Blood ammonia
`● Anion gap
`● Liver transaminases, alkaline phosphatase, bilirubin, prothrombin time
`● Blood lactate and pyruvate
`● Arterial blood gas
`● Serum and urine amino acids
`● Urine organic acids
`● Urine quantitative orotic acid
`● Plasma carnitine (total, free, and esterified)
`● Plasma acylcarnitine profile
`Treatment: Prevention of catabolism and ammonia accumulation
`● Intravenous dextrose (20% or 25%)
`● No exogenous protein for 24 to 48 h
`● Use continuous insulin drip if hyperglycemic
`● Intravenous lipid (once fatty acid oxidation disorders excluded)
`● Provide total calories of approximately 100 to 120 kcal/kg per day
`Treatment: Medications
`● Sodium benzoate and sodium phenylacetate
`● Arginine hydrochloride 10%*
`● Lactulose 2.5 mL NG/PO tid prn
`● Neomycin 50 mg/kg per day PR q 6 h†
`Treatment: Other measures
`● Central vascular access
`● Correction of hypovolemia, anemia, and possible acidosis
`● Treatment of underlying infection
`● Intubation and ventilation (target PaCO2 of 30 to 35 mm Hg)
`● Urinary catheter (for monitoring of urine output)
`● Hemodialysis
`
`*Acidosis may occur; arterial blood gases should be examined after loading dose.
`†Only in neonates ⬎2 days old.
`
`vehicle for waste nitrogen excretion
`in AS deficiency (citrullinemia), as
`long as sufficient arginine is supplied
`(Fig. 1). (17)(18) However, citrulline
`contains only one waste nitrogen
`atom, and a high percentage of filtered
`citrulline is reabsorbed, so urine excre-
`tion is relatively poor. (18)
`
`Amino Acylation Products
`HIP is an excellent metabolite for
`renal excretion because its
`renal
`clearance is five times the glomerular
`filtration rate. (17) HIP biosynthesis,
`by conjugation of BZ with glycine, is
`accomplished by the action of mito-
`
`chondrial matrix enzymes (benzoyl
`thiokinase
`and a glycine-specific
`N-acyltransferase) (Figs. 1 and 2).
`(13)(16) Similarly, PAGN is formed
`by sequential action of phenylacetyl
`thiokinase and a glutamine-specific
`N-acyltransferase. (12)(13) Because
`PA has the ability to conjugate glu-
`tamine,
`forming PAGN (a com-
`pound that contains two nitrogen at-
`oms), its nitrogen-scavenging ability
`was hypothesized to be twice as ef-
`fective as BZ (which contains one
`nitrogen atom).
`(18)
`In 1979,
`Brusilow and colleagues (17) sug-
`gested using combined therapy with
`
`pharmacology review
`
`NAPA and NABZ for treating hyper-
`ammonemic coma.
`
`Initial Clinical Trials of NAPA
`and NABZ
`The potential of alternative pathway
`therapy was demonstrated initially in
`1980. A clinically stable 17-year-old
`girl who had carbamyl phosphate
`synthetase deficiency excreted signif-
`icant amounts of HIP and PAGN in
`the urine after NABZ (6.25 g/d) or
`PA (6.4 g/d) was administered
`orally. Subsequent administration of
`NABZ (250 to 350 mg/kg, either
`orally or intravenously) in four pa-
`tients who had UCD and were in
`hyperammonemic comas resulted in
`a prompt decrease in plasma ammo-
`nia concentrations and clinical im-
`provement in each case. (20) In a
`further study, a single oral or intrave-
`nous dose of NABZ (250 to
`500 mg/kg) lowered plasma ammo-
`nia concentrations in five of seven
`patients who had hyperammonemia
`(two of three neonates and four of
`five older children). (9) In another
`study, (21) 26 patients were treated
`with
`intravenous NABZ (250
`mg/kg loading dose, followed by
`250 to 500 mg/kg per day continu-
`ous infusion) and arginine hydro-
`chloride (800 mg/kg loading dose,
`followed by 200 to 800 mg/kg per
`day) during acute neonatal hyperam-
`monemia. PD was required during
`neonatal hyperammonemic coma ep-
`isodes in 20 of 23 patients. There
`were three neonatal deaths. It was
`concluded that alternative pathway
`therapy (NABZ and arginine supple-
`mentation), combined with dietary
`restriction of protein and provision
`of
`supplemental
`calories
`in an
`amount no less than 100 kcal/kg
`per day, can prolong survival and
`improve clinical outcome in chil-
`dren who have UCDs.
`
`NeoReviews Vol.7 No.9 September 2006 e489
`
`Page 4 of 10
`
`

`

`pharmacology review
`
`NAPA/NABZ
`In 1984, Brusilow and colleagues
`(22) reported the results of a thera-
`peutic protocol for the treatment of
`hyperammonemia caused by UCDs
`using a combination of intravenous
`NAPA plus NABZ. The initial clini-
`cal trial of combined therapy in-
`volved 12 episodes of hyperam-
`monemia in seven children ages 3 to
`26 months who had a variety of
`UCDs. The plasma ammonia con-
`centrations decreased to normal or
`nearly normal levels in all patients,
`except in a 9-month-old boy who
`had OTC deficiency and the highest
`pretreatment ammonia value and the
`longest delay between symptom on-
`set and therapy.
`The combination of NAPA (10%)
`and NABZ (10%) is an intravenously
`administered drug approved by the
`FDA as adjunctive therapy for the
`treatment of acute hyperammonemia
`and associated encephalopathy in pa-
`tients who have urea cycle enzyme
`deficiencies. The concomitant use of
`NAPA/NABZ with protein restric-
`tion, high caloric nutrition, arginine
`hydrochloride, and hemodialysis in
`neonatal hyperammonemia helps to
`increase waste nitrogen excretion
`through the formation of HIP and
`PAGN by two different pathways
`(Figs. 1 and 2). Pharmacogenetic
`factors partly determine the activity
`of enzymes responsible for formation
`of HIP and PAGN and, therefore,
`play a role in determining the indi-
`vidual rate of nitrogen removal. He-
`modialysis is recommended in cases
`of severe hyperammonemia or if am-
`monia concentrations are not signif-
`icantly reduced within 4 to 8 hours
`after starting NAPA/NABZ therapy.
`When a diagnosis of hyperam-
`monemia is established in a neonate,
`NAPA/NABZ infusion should be
`started as soon as possible. A loading
`dose is administered over 90 min-
`utes, followed by a similar mainte-
`
`Figure 1. The urea cycle and alternative pathway therapy. ALⴝargininosuccinic acid
`lyase, ARGⴝarginase, ASⴝargininosuccinic acid synthetase, CPSⴝcarbamyl phosphate
`synthetase, NAGSⴝN-acetylglutamate synthetase, OTCⴝornithine transcarbamylase,
`ATPⴝadenosine triphosphate
`
`Figure 2. Mechanism of nitrogen scavenging by sodium benzoate and sodium
`phenylacetate. Hippurate and phenylacetylglutamine are formed by conjugation of
`benzoate with glycine and phenylacetate with glutamine, respectively. These reactions
`are performed by specific liver and kidney N-acyltransferases (see text). *ⴝnitrogen
`atoms excreted
`
`e490 NeoReviews Vol.7 No.9 September 2006
`
`Page 5 of 10
`
`

`

`pharmacology review
`
`Table 5. Recommended NAPA/NABZ and Arginine HCI Dosages for
`Treating Neonatal Urea Cycle Defects
`
`Arginine HCI
`
`Administration
`
`NAPA]
`NABZ
`
`Patients weihin O to 20 k
`
`Sodium
`Dextrose
`Arginine HCI
`Injection,10% Injection, 10% Phenylacetate Benzoate
`
`Sodium
`
`Injection. 10%
`
`
`‘
`‘
`r“ l V‘s“
`
`
`
`thetase Deficlency
`Arginlnosucelate Syn
`Loading Dose: over 90 to 120 min 2.5 mng 6.0 mL/kg
`25 mL/kg
`250 mg/kg
`250 mg/kg 600 mg/kg
`Maintenance Dose: over 24 h
`250 m k
`2.5 mL/k
`
`
`
`Loading Dose: over 90 to 120 min 2.5 mL/kg 2.0 mL/kg
`Maintenance Dose: over 24 h
`2.5 mng 2.0 mL/kg
`
`Deficiency
`Ornithine Trnsearbamyl
`25 mL/kg
`250 mg/kg
`250 mg/kg 200 mg/kg
`250 mg/kg 200 mg/kg
`250 mg/kg
`25 mL/kg
`
`
`
`nance
`
`dose
`
`administered
`
`over
`
`24 hours (Table 5). NAPA/NABZ is
`diluted in sterile 10% dextrose to a
`
`dose of 250 mg/kg in both loading
`and maintenance infusions. Because
`
`of the saturable pharmakokinetics of
`PA, no more than one loading dose
`of NAPA/NABZ is recommended
`regardless of the initial ammonia
`concentration. The maintenance in—
`fusion can be continued until ammo—
`nia values are within normal limits.
`
`Arginine hydrochloride 10% can be
`mixed in the same dextrose solution
`
`as NAPA/NABZ. NAPA/NABZ
`should be administered through a
`central
`line because extravasation
`
`may cause irritation, burns, and ne-
`crosis.
`
`Pharmacokinetics
`
`Pharmacokinetics is the process by
`which a drug is absorbed, distrib—
`uted, metabolized, and eliminated by
`the body (ie, what the body does to
`the drug). Both PA and BZ show
`nonlinear
`saturable,
`elimination,
`with a decrease in clearance with in-
`
`creased dose. Therefore, following
`established treatment protocol dos-
`
`Page 6 of 10
`
`ing guidelines is important. Brusilow
`and associates (22) studied the phar—
`macokinetics of NAPA and NABZ in
`
`two children who had carbamyl
`phosphate
`synthetase
`deficiency,
`ages 5 months and 1 year. Similar to
`findings in adults, the levels of PA
`and El peaked at the same time, and
`the level of BZ decreased faster. PA
`
`levels were initially higher than BZ
`levels and remained so throughout
`the study. HIP reached a peak earlier
`than PAGN, but PAGN levels re—
`mained high for a longer period
`compared with HIP in both patients.
`Urinary HIP nitrogen (18% to 57%
`ofwaste nitrogen) and urinary PAGN
`nitrogen (15% to 53% of waste nitro-
`gen) combined accounted for ap-
`proximately 60% of the “effective”
`urinary waste nitrogen.
`No pharmacokinetic studies on
`NAPA/NABZ performed
`exclu—
`sively in neonates have been pub—
`lished. However, Green and associ-
`ates (23) monitored the disposition
`of intravenous NABZ alone in new—
`
`borns who had hyperammonemia
`(n=4) following administration of
`460 mg/kg per day in four divided
`
`doses. An eight—fold range in serum
`BZ concentrations was noted among
`treated neonates. The elimination
`half-life of BZ was 2.8131 hours.
`
`The total plasma clearance of BZ was
`1.00:0.61 mg/kg per minute, with
`most of the clearance attributed to
`
`glycine conjugation in three of four
`neonates. The excreted total of BZ
`and HIP was 84i3l% ofthe admin—
`istered BZ. One neonate who had
`reduced renal clearance excreted
`
`only 12% of BZ as HIP. In this case,
`PD was the major route of BZ clear—
`ance. (23) Intravenous infusions of
`BZ and PA (given on different days)
`were administered to five children
`
`who had lysinuric protein intolerance
`and were clinically stable during the
`period of study. (24) Plasma BZ lev-
`els peaked at 6.0 mmol/L (range,
`5.2 to 7.0 mmol/L) 2 hours after the
`start of the infilsion (2.0 mmol/kg
`over 90 min) and decreased linearly,
`with a mean half—life of 273 minutes.
`
`Plasma HIP levels peaked 120 min—
`utes after the start of the infusion at
`
`0.24 mmol/L (range, 0.14 to
`0.40 mmol/L) and remained stable
`for 3 hours. Less than 2% of the
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`administered dose of BZ appeared
`unchanged in the urine. Plasma PA
`levels also peaked at 120 minutes and
`decreased similarly to BZ (half-
`life⫽254 min), although peak levels
`were lower (4.8 mmol/L; range,
`3.7 to 6.1 mmol/L). Plasma PAGN
`levels peaked at 270 minutes, with a
`mean concentration of 0.48mmol/
`L (range, 0.22 to 1.06 mmol/L).
`Forty percent (range, 15% to 110%)
`of infused PA was excreted as PAGN
`in 24 hours. (24)
`
`Pharmacodynamics and
`Outcome Studies
`Pharmacodynamics is the process of
`biochemical and physiologic effects
`of a drug, the mechanisms of drug
`action, and the relationship between
`drug concentration and effect (ie,
`what the drug does to the body).
`Treatment with NAPA/NABZ re-
`sults in decreased plasma ammonia
`concentrations and improved neuro-
`logic status in most cases, although if
`severe hyperammonemia is present,
`alternative pathway therapy may not
`have any appreciable effect. (14)
`(22)(23)(24)(25)(26)(27) A study
`of 26 children found a survival of
`85% following treatment with alter-
`native pathway therapy for 7 months
`to 5 years. (21) A total of 64 post-
`neonatal episodes of hyperammone-
`mia occurred in 19 of 26 patients,
`with excessive protein intake, inter-
`ruption of medications, and intercur-
`rent infections being common causes
`of metabolic decompensation. Of
`the 23 survivors, 10 had normal de-
`velopment, 7 had mild mental retar-
`dation (intelligence quotient [IQ]
`52 to 68), and 6 had moderate-to-
`severe mental retardation (IQ ⬍52).
`Msall and colleagues (28) reported
`that rapid treatment with NAPA/
`NABZ substantially improved sur-
`vival compared with historic con-
`trols. One-year survival was 92% in
`
`e492 NeoReviews Vol.7 No.9 September 2006
`
`children who had UCDs treated with
`protein restriction and alternative
`pathway therapy. Mental impairment
`was common, with 79% of children
`having developmental disabilities at
`12 to 74 months of age. Maestri and
`associates (25) concluded that in in-
`fants at risk for hyperammonemia
`caused by UCDs based on family his-
`tory, prospective treatment with
`NAPA/NABZ is effective in avoid-
`ing hyperammonemic coma and re-
`sults
`in more favorable outcome
`compared with patients who are res-
`cued from hyperammonemic coma.
`The brief period of prospective treat-
`ment while awaiting results of confir-
`matory diagnostic studies does not
`appear to have any adverse effect on
`the growth and development of in-
`fants who do not have the diagnosis.
`
`Adverse Reactions
`Experiments in rats and a mouse
`model of OTC deficiency (sparse-fur
`mouse) demonstrated that BZ has
`the potential to inhibit fatty acid ox-
`idation and pyruvate dehydrogenase
`activity, possibly by depleting stores
`of hepatic glycine, free CoA, and
`acetyl-CoA.
`(29)(30)(31)(32)(33)
`In the sparse-fur mouse, supplemen-
`tation with carnitine counteracted
`the adverse effects of higher doses of
`BZ. The levels of free CoA, acetyl-
`CoA, and ATP in both brain and liver
`increased following carnitine admin-
`istration. (34) PA is neurotoxic in a
`rat model, possibly through deple-
`tion of acetyl-CoA. (35) PA also in-
`hibits 5-hydroxytryptophan decar-
`boxylase in guinea pig kidneys and
`dihydroxyphenylalanine decarboxyl-
`ase in beef adrenal medulla. (36)(37)
`Despite these findings
`in animal
`models, NABZ and NAPA are re-
`markably nontoxic in humans when
`used in the treatment of UCDs at the
`recommended doses. (14)(18)(38)
`Because of the difficulty in distin-
`guishing symptoms related to hyper-
`
`ammonemia from symptoms caused
`by a reaction to medication, adverse
`effects are similarly difficult to at-
`tribute directly to alternative path-
`way therapy. Oral BZ therapy has
`been associated with nausea and
`vomiting, (21)(26) but overall toxic-
`ity appears to be low as long as stan-
`dard dosing guidelines are followed.
`(38) The use of benzyl alcohol as a
`bacteriostatic agent in neonatal in-
`tensive care units has resulted in se-
`vere metabolic acidosis, lethargy pro-
`gressing to coma,
`seizures, and
`death. BZ and HIP, breakdown
`products of benzyl alcohol, were
`identified in the urine of affected ne-
`onates. (39) A theoretical concern
`related to BZ use in neonates is its
`potential ability to displace bilirubin
`from high-affinity albumin binding
`sites. (23) However, to our knowl-
`edge, no cases have been reported of
`significant hyperbilirubinemia or ker-
`nicterus attributable to BZ use.
`No adverse effects, other than an
`unpleasant odor, were reported in
`healthy humans and two patients
`who had UCDs receiving between
`1 and 10 g of PA. (38)(40) Intrave-
`nous PA was not associated with any
`clinical toxicity during bolus dosing,
`but vomiting, confusion, and leth-
`argy occurred in three of 17 cancer
`patients who had solid tumors dur-
`ing the course of a 14-day continu-
`ous infusion. A strong PA odor also
`was noticeable on patients’ clothes
`and on examiners’ hands following
`physical examination. (41) A further
`oncology trial of PA reported som-
`nolence,
`fatigue, headache,
`light-
`headedness, and dysgeusia associated
`with PA concentrations between
`3.7 and 7.5 mmol/L. (42)
`The most common adverse reac-
`tion reported with NAPA/NABZ
`use is vomiting, occurring in about
`9% of patients. (21) In a study of
`healthy adults, nausea, vomiting, and
`somnolence were reported following
`
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`administration of NAPA/NABZ in
`doses used to treat hyperammone-
`mia. (43) Simell and associates (24)
`induced hyperammonemia in five pa-
`tients who had lysinuric protein in-
`tolerance and administered alanine
`with either intravenous PA or BZ.
`They reported dizziness, nausea, and
`vomiting in four patients at the end of
`the infusion. Mean peak plasma levels
`of 6 mmol/L (BZ) and 4 mmol/L
`(PA) were documented. (24)
`The most significant adverse ef-
`fects and toxicity related to NAPA/
`NABZ use have occurred in cases of
`inadvertent overdosage. Continuous
`intravenous infusion rates causing
`plasma PA concentrations that satu-
`rate the capacity of conversion of PA
`to PAGN result in rapid phenylace-
`tate accumulation and subsequent
`toxicity. (41) Praphanphoj and co-
`workers (44) reported three patients
`ages 2 to 6 years who were given
`inappropriately high doses of intrave-
`nous NAPA/NABZ (915 mg/kg
`over 12 h, 1,750 mg/kg over 18 h,
`and 750 mg/kg over 10 h). The
`children had plasma BZ and PA levels
`of
`approximately
`10 mmol/L
`4 hours after infusion and developed
`altered mental
`status, Kussmaul
`breathing, metabolic acidosis, cere-
`bral edema, and hypotension. Two of
`the three patients died, and one sur-
`vived after hemodialysis. (44)
`
`Adjunctive Therapeutic
`Modalities
`In addition to NAPA/NABZ, the
`importance of providing appropriate
`nutrition, protein restriction, argi-
`nine hydrochloride, and hemodialy-
`sis or continuous venovenous hemo-
`filtration for treating neonatal hyper-
`ammonemia cannot be overempha-
`sized. Central access is critical to pro-
`vide high-dextrose fluids and intrave-
`nous lipid, with the goal being to
`administer approximately 100 to
`120 kcal/kg per day. (27) An insulin
`
`drip often is needed to control hyper-
`glycemia and promote anabolism.
`Protein should be withdrawn imme-
`diately and reintroduced slowly after
`24 to 48 hours. Alternative pathway
`therapy with arginine hydrochloride
`infusion works synergistically with
`NAPA/NABZ, so the arginine hy-
`drochloride bolus and maintenance
`infusions typically are administered
`simultaneously with NAPA/NABZ
`(Table 5). It is crucial to transfer the
`neonate who has confirmed hyper-
`ammonemia to a center that has ex-
`perience in all aspects of UCD man-
`agement,
`including nutrition and
`hemodialysis, or other forms of con-
`tinuous renal replacement therapy
`(such as continuous venovenous he-
`mofiltration or continuous veno-
`venous hemodiafiltration) as soon as
`possible. (45)
`
`Use of NAPA/NABZ for
`Treatment of Other
`Conditions
`The use of NAPA/NABZ to treat
`other conditions that can cause neo-
`natal hyperammonemia, such as or-
`ganic acidemias, fatty acid oxidation
`disorders, and transient hyperam-
`monemia of the newborn, has not
`been studied in detail. However,
`these conditions may be difficult to
`distinguish from UCDs in some in-
`stances.
`(46)(47) Clinicians have
`used NAPA/NABZ to treat non-
`UCD conditions with variable effi-
`cacy. (48)(49)
`
`Conclusion
`NAPA/NABZ is effective, in con-
`junction with appropriate high-
`calorie nutrition, protein restriction,
`intravenous arginine hydrochloride,
`and hemodialysis, in the treatment of
`neonatal hyperammonemia caused
`by UCDs. Survival rates and neuro-
`logic outcomes of patients are im-
`proved compared with historical out-
`comes. NAPA/NABZ also can safely
`
`pharmacology review
`
`be used in prospective treatment of
`infants at risk for a UCD because of a
`positive family history who have not
`undergone prenatal diagnostic test-
`ing. Because of nonlinear pharmaco-
`kinetics and the potential for accu-
`mulation of especially PA with higher
`doses of NAPA/NABZ, clearly writ-
`ten medical prescriptions and cross-
`checking of drug dosage are impor-
`tant
`safeguards. In addition,
`the
`immature liver function of neonates
`merits careful observation and mon-
`itoring of infants because of the im-
`portance of liver conjugation reac-
`tions for both NABZ (with glycine to
`form HIP) and NAPA (with glu-
`tamine to PAGN). Because neonates
`who have severe hyperammonemia
`may not improve following NAPA/
`NABZ administration, the impor-
`tance of immediate transfer to a cen-
`ter that has experience in caring for
`such children, including the ability to
`perform hemodialysis, cannot be
`overemphasized.
`
`ACKNOWLEDGMENTS. This
`re-
`view was supported by a grant from
`the Packard Children’s Health Fund
`for AKN.
`
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