SCIENTIFIC DISCUSSION
`
`This module reflects the initial scientific discussion for the approval of Ammonpas. This
`scientific discussion has been updated untill November 2001. For information on changes after
`this date please refer to module 8B.
`
`1.
`
`Introduction
`
`Ammonaps, sodium phenylbutyrate (PB), is a new active substance. It is indicated as adjunctive
`involving deficiencies of
`the chronic management of urea cycle disorders,
`therapy
`in
`carbamylphosphate synthetase, ornithine transcarbamylase, or argininosuccinate synthetase. It is
`indicated in all patients with neonatal-onset presentation (complete enzyme deficiencies, presenting
`within the first 28 days of life). It is also indicated in patients with late-onset disease (partial enzyme
`deficiencies, presenting after the first month of life) who have a history of hyperammonaemic
`encephalopathy.
`
`The dossier submitted in support of the application comprises data generated by the applicant: all
`chemical/pharmaceutical data, the two mutagenicity studies for Part III, and for Part IV, the
`bioequivalence study and a review of the US IND/NDA programme. Additional information was
`available from published literature.
`
`Urea cycle disorders (UCD) are inherited deficiencies of one of the enzymes involved in the urea
`cycle, by which ammonium is converted to urea. Ammonium is highly toxic to nerve cells and
`hyperammonaemia may result in metabolic derangement, leading to anorexia, lethargy, confusion,
`coma, brain damage, and death.
`
`The most severe forms of UCDs occur early in life (complete enzyme deficiencies). The classic
`neonatal presentation of all the UCD (with the exception of arginase deficiency) is quite uniform and
`includes, after a short symptom-free interval of one to five days, poor feeding, vomiting, lethargy ,
`muscular hypotonia, hyperventilation, irritability and convulsions. Without rapid intervention, coma
`prevails as the condition worsens and leads eventually to deaths. Later onset forms of UCD occur in
`infancy, at puberty, and in adults subject to physiological stress. In the late onset forms, more subtle
`symptoms have been described including vomiting, migraine-like headache, changes in the level of
`consciousness and neurological signs, such as
`lethargy, somnolence,
`irritability, agitation,
`combativeness, disorientation, ataxia and visual impairment. Seizures are a late complication. Finally,
`delayed physical growth and delay in mental development are common. In female patients with
`ornithine transcarbamy lase deficiency, who are heterozygous, the condition is less severe and they
`may remain undiagnosed well into adult life.
`
`In the absence of systematic screening, the incidence of UCD is difficult to assess and various
`estimates are found in the literature. On this basis, it is estimated that the overall incidence of all urea
`cycle disorders has been defined as 1 per 8,200 births.
`
`The treatment strategies used are to reduce dietary protein intake, and to provide an alternative vehicle
`to urea for the excretion of nitrogen waste. Currently none of the possible treatments for
`hyperammonaemia are approved in Europe. Enzyme replacement therapy through liver transplantation
`provides an additional treatment option. In most patients this procedure has markedly improved their
`metabolic abnormalities and permitted a normal protein intake, however, transplantation for UCD is a
`relatively recent treatment option and its long-term benefits are as yet unknown.
`
`Sodium phenylbutyrate is a prodrug and is rapidly metabolised to phenylacetate. It promotes the
`synthesis of phenylacetylglutamine, which then serves as a substitute vehicle for waste nitrogen
`excretion. The recommended dose is:
`
`450 - 600 mg/kg/day in neonates, infants and children weighing less than 20 kg
`9.9- 13.0 g/m2/day in children weighing more than 20 kg, adolescents and adults.
`The safety and efficacy of doses in excess of 20 g/day has not been established.
`
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`Par Pharmaceutical, Inc. Ex. 1019
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`

`2.
`
`Chemical, pharmaceutical and biological aspects
`
`Composition
`
`Ammonaps is presented as tablets and granules containing sodium phenylbutyrate. Two standard and
`simple pharmaceutical formulations of sodium pheny lbutyrate were produced with commonly used
`excipients. The tablets (500 mg) contain approximately 74% active substance and the granules provide
`940 mg sodium phenylbutyrate/g granules.
`
`In order to dose accurately and especially for smaller amounts required for infants, three measuring
`spoons have been introduced for the granules, giving doses of 0.95 g, 2.9 g and 8.6 g. The overall
`uniformity of doses obtained from the three measuring spoons is acceptable and the individual weights
`are within the Ph. Eur. limit of 10% for single-dose powders.
`
`The proposed container for both granules and tablets is a high density polyethylene (HDPE) bottle
`with a desiccant unit, closed with a polypropylene caps (child resistant). The materials have been
`adequately tested for conformance to USP requirements.
`Active substance
`
`Pharmaceutical data on the active substance have been presented in an EDMF (European Drug Master
`File). Sodium phenylbutyrate is off-white to slightly yellow powder, which is soluble in water. A four(cid:173)
`step synthetic process with acceptable in-process controls manufactures it. Process validation data
`show the synthesis to be under control. Satisfactory specifications were provided for the starting
`material, solvents, reagents and intermediates. The manufacturer of the active substance has
`adequately validated the analytical methods used. The manufacturer of the finished product to re-test
`the active substance uses the same methods; full re-validation is to be carried out on these methods
`and results provided.
`
`Sodium phenylbutyrate has a simple structure and presents no polymorphic forms. The pathway of
`synthesis has confirmed the evidence of its chemical structure, by elemental analysis, 1 RNMR and IR
`spectroscopy.
`
`The specification includes tests for appearance, bulk density, water content, identifcation by IR and
`HPLC, heavy metals, pH, assay and impurities. Three main related substances are specified: a(cid:173)
`tetralone, 3-benzoylpropionic acids and 4-cyclohexylbutyric acids. Further impurities (e.g. isomer 2-
`phenylbutyric acid) can be detected by a GC or HPLC assay method but have not been found in the
`active substance. While the limits for impurities have been toxicologically accepted, it is suggested
`that in view of the high doses to be given (> 2 g/day), limits should be reviewed and tightened when
`further batch data are available. Residual solvents are also specified at a suitable limit in agreement
`with CPMP/ICH guidance.
`
`Analytical results from three batches show compliance with the specification and indicate suitable
`uniformity.
`
`The active substance (3 batches) was tested for up to 12 months under real-time (25°C/60%RH) and
`accelerated condition ( 40°C/75%RH). It was also tested in solvent and solution, under the influence of
`pH and oxidative conditions. The shelf-life specification includes appearance, assay, impurities, pH
`and water. Increases in water content were observed but are not linked to the increases in 3-
`benzoy I propionic acid also seen in stability batches and are not detrimental to the stability of sodium
`phenylbutyrate. A 12-month retest period can be approved.
`Other ingredients
`
`Satisfactory information has been provided on the excipients. All excipients will be released against
`relevant Ph.Eur. Monographs. For those excipients derived from tallow (i.e. magnesium and calcium
`stearate), a TSE declaration was provided in accordance with the EU requirements (Commission
`Decision 97/534/EC).
`
`2/12
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`

`Product development and finished product
`
`No detailed pre-formulation studies were performed. The tablets and granules are manufactured using
`simple formulations based on commonly used excipients, standard pharmaceutical equipment and
`processes. The function of the excipients is stated.
`
`Forced degradation studies have been conducted under extreme temperature and acidic conditions.
`They indicate a rise in 3-benzoylpropionic acid level, as well as some degradants not detectable by
`HPLC, but these extreme conditions do not reflect the product as marketed. Results of up to 0.006%
`w/w were found from batches tested for 3-benzoylpropionic acids.
`
`Batches manufactured at different sites have been used in clinical trials and bioequivalence studies.
`Results of a three-way crossover study in healthy volunteers receiving 5 grams doses of tablets or
`granules indicate that the bioavailability of the granule formulation is less than that of the tablets, but
`remains within the usual criterion of± 20%. This will be further discussed in Part IV.
`
`The manufacturing processes for both granules and tablets consist of multi-stage blending,
`compaction, granulation, and compression as the final step for tablets. The processes are satisfactorily
`described.
`
`Mixing times, equipment conditions and in-process controls are described for both formulations
`accordingly (weight, thickness, hardness, friability for the tablets, fill volume for the granules and bulk
`and tapped density testing for both tablet and the granules) and their parameters are specified within
`acceptable limits. Results from clinical (7 and 5 batches for granules and tablets, respectively) and
`production (2 batches for granules and tablets) batches indicate acceptable batch-to-batch consistency.
`
`A revised finished product specification (for both the site of manufacture and the site of batch release)
`has been provided in compliance with EU requirements. Control tests on the finished product use
`adequately validated methods and include requirements for appearance, identification of active
`substance, assay and impurities determination, bulk density testing for granules, and average weight,
`uniformity of weight, disintegration and dissolution for the tablets. The microbiological quality is
`controlled in accordance with Ph. Eur., but is proposed as a non-routine method.
`
`The dissolution medium, previously simulated intestinal fluid, has been changed to water. The
`dissolution specification has been tightened to 80% in 45 minutes but this should be reviewed again in
`the light of further data. Dissolution results using both media show slightly greater dissolution in
`water, but dissolution is essentially complete in both media at the same time. The disintegration limit
`is set slightly higher than usual (at 20 min); this is acceptable as the results do not impact adversely on
`dissolution.
`
`A commitment is given by the applicant to submit certificates of analysis for the first three production
`batches, tested to the EU specifications. Limits for impurities will be reviewed when further batch data
`are available.
`
`On the basis of the inspection carried out at Pharmaceutics International Inc on 13-15 May 1998, the
`inspection report confirmed that the operations are in general compliance with the principles and
`guidelines of GMP (see the Annex II).
`
`Stability studies have been carried out at 25°C/60%RH up to 24 and 36 months on batches of granules
`and tablets made by Pharmaceutics International, and at 40°C/75%RH for 6 months. Shelf-life content
`limits of 93-107% have been accepted for the finished products on the basis of the variability in
`results, though no degradation appears to occur. The limits should be reviewed again when further
`stability data are available. The analytical methods used are those for routine finished product testing
`or similar, validated methods. No change of appearance was observed. Content and impurity levels
`remain within the proposed limits as specified. Satisfactory stability data for the full shelf-life have
`been provided and based on the resulting data, a 2-year shelf life is acceptable for both granules and
`tablets when stored below 30°C.
`
`•
`
`Discussion on chemical, pharmaceutical and biological aspects
`
`Ammonaps granules and tablets are conventionally formulated and manufactured using standard
`pharmaceutical technology. A suitable specification has been submitted for the active substance. The
`limits for impurities have been toxicologically accepted (see Part III). A single specification for each
`
`3/12
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`

`

`finished product formulation is also proposed, with revised specification for dissolution parameters
`and impurity limits. In line with the requirements for the active substance, the impurity limits should
`be reviewed when further data are available.
`
`Overall, the chemical-pharmaceutical dossier is generally acceptable. The company was however
`requested to provided, within the agreed timeframe, additional data, which have not been satisfactorily
`resolved; these are defined in the follow-up measures as listed in the company's undertaking letter (see
`section II.3 of this report).
`
`3.
`
`Toxico-pharmacological aspects
`
`Pharmacodynamics
`
`Pharmacodynamic effects relating to the proposed indications are as outlined in section 4 (Clinical
`pharmacology /Pharmacodynamics).
`
`General pharmacodynamics - A number of studies seem to indicate the ability of PB to inhibit tumour
`growth in vitro, and that phenylacetate and probably phenylbutyrate have neuroinhibitory and
`neurotoxic potential under the in vitro and ex-vivo conditions studied.
`
`Two rat models of human phenylketonuria were developed, one involved exposure to PA injected s.c.
`twice daily from day 2-28 of life. In the other, pregnant rats were exposed to P A during gestation.
`Reduced brain weight, abnormalities in learning, and in neurotransmitter uptake are consistently
`noted. It was argued that high concentrations are unlikely during therapeutic use of PB because of
`poor transfer across the adult blood-brain barrier. The implications of these findings with respect to
`human foetal brain are unknown (see also below- Reproductive and development toxicity studies)
`
`Pharmacokinetics
`
`Studies in the juvenile rat, where subcutaneous administration was used, and in the adult cat, where
`intravenous administration was used, have been performed. Even though pharmacokinetic data after
`oral administration are not available, it can be expected that being an organic acid, PB will be rapidly
`and extensively absorbed after oral administration. It is converted to its active metabolite, P A by beta(cid:173)
`oxidation. In single subcutaneous dose studies from birth to maturity in rats, P A penetrated tissues
`rapidly and extensively, with tissue levels usually equivalent to those in blood. Like other organic
`acids, P A is actively excreted in urine by tubular secretion as the amino acid conjugate.
`Toxicology
`Single dose toxicity - No single dose toxicity studies have been carried out. However, sufficient
`information is available from the animal pharmacology above. The doses of P A given in these studies
`were low. Taken together, the results of the studies suggest that single doses of PA by both the
`intravenous and subcutaneous routes are well tolerated.
`
`Repeated-dose toxicity - There are no repeated dose studies available. However, information available
`from the animal pharmacology above makes a convincing case that parenteral administration of
`phenylacetate causes impairment of brain development in the immature rodent. Because phenylacetate
`can cross into human CNS, the observations in rodents should be considered a potential hazard for the
`therapeutic use of PB.
`
`Carcinogenicity - Carcinogenicity studies have not been performed. These deficiencies are not
`considered to be an impediment to the granting of a Marketing Authorisation in view of ICH-S1A:
`guideline on the need for carcinogenicity studies of pharmaceuticals.
`
`Genotoxicity and mutagenicity - A bacterial reverse mutation assay (Ames test, plate incorporation
`method) was conducted with PB at concentrations in the range of 52-5000 J.Lg/plate, using five strains
`of Salmonella Typhimurium, in the presence and absence of rat liver microsomal enzymes (S9). No
`cytotoxicity or revertant colonies were observed at the top dose. A bone marrow micronucleus test
`was also conducted using rats of both sexes (5 animals/sex/group; PB 878-1568-2800 mg/kg single
`oral gavage). Deaths occurred in top dose (7/10, at 2800 mg/kg) and mid-dose (2/10, at 1568 mg/kg)
`groups. The frequency of micronucleated cells was not significantly different from the negative
`control at any dose level at either the 24 hour or the 48 hour harvest.
`
`4/12
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`

`

`Attention should be drawn to the fact that the Ames test did not comply with the ICH-requirements
`(i.e. two recommended strains of E. coli were not included to pick-up A-T and G-C base pair
`mutations) and there are no pharmacokinetic data in either rat or man to validate the in vivo study in
`terms of reaching adequate plasma levels. Despite these deficiencies, the results of both studies did not
`give raise to any evidence of mutagenic potential.
`
`Reproductive and development toxicity studies - Studies on administration to pregnant rodents indicate
`that CNS damage may occur in animals exposed in utero. However, as drug administration did not
`commence until day 9 of gestation, after the main period of organogenesis, these studies are not
`optimal for the assessment of teratogenic potential. In female pregnant rats, spontaneous abortions
`occurred, birth weight of the offspring was significantly lower than in controls, weight gain of the
`pups over the lactation period was reduced, and brain weight at sacrifice was low. It also seems likely
`that spermatogenesis and therefore fertility would be affected in the male rat.
`
`Impurities- In the active substance, a-tetralone, 3-benzoylpropionic acid and 4-cyclohexylbutyric acid
`are the potential impurities identified. According to the ICH requirements, the threshold for
`toxicological qualification of impurities is 0.05% (w/w) and of degradation products is 0.1 %, when the
`total daily intake exceeds 2 g, as in the case of Ammonaps. The limits for cyclohexylbutyric acid and
`for other impurities in the active substance and in the release specification for the tablets and granules
`are higher than the threshold (at 0.1 %), but the limits have been found to be toxicologically
`acceptable. No adverse events would be expected as a result of these impurities, but the applicant is
`required to submit further data from manufacturing batches and these data will be reviewed (see also
`Part II).
`
`•
`
`Summary and conclusion on preclinical pharmacology and toxicology:
`
`There are no formal toxicity studies; no overt toxicity was noted in a review of the data available. A
`bacterial reverse mutation and a rat bone marrow micronucleus test have been carried out with sodium
`phenylbutyrate and did not give rise to any evidence of mutagenic potential. The available data
`indicate that PB is fetotoxic, affecting mainly the brain; effects on reproduction and organogenesis
`have not been conventionally investigated. This has been dealt with in the SPC, where pregnancy is
`contra-indicated and an explanation is given in the appropriate section of the document.
`
`The deficiencies of the pre-clinical section of the dossier should be viewed in the light of the CPMP
`recommendation for an approval under exceptional circumstances. As required for an authorisation
`under exceptional circumstances, appropriate information is provided in the product information to
`draw the attention of the medical practitioner to the fact that the currently available data concerning
`the medicinal product in question is inadequate in certain specified respects. The conditions for which
`this medicinal product would be indicated would fall within the scope of the Proposed European
`Parliament and Council Regulation (EC) on Orphan Medicinal Products.
`
`4.
`
`Clinical aspects
`
`Ammonaps, sodium phenylbutyrate (PB), is a new active substance with the proposed therapeutic
`indication "adjunctive therapy in the chronic management of urea cycle disorders, involving
`deficiencies of carbamy 1 phosphate synthetase, ornithine transcarbamy lase or argininosuccinate
`synthetase". Urea Cycle Disorders (UCD) are inherited deficiencies of one of the enzymes involved in
`the urea cycle, by which ammonium is converted to urea. Excess dietary protein and the nitrogenous
`substances produced by endogenous protein turnover are normally metabolised to yield energy and the
`by-product ammonium, which is excreted in the urine as urea. Each pass through this cycle results in
`the elimination of one molecule of urea, which contains two atoms of waste nitrogen. Due to
`deficiencies of the urea cycle, the conversion of ammonium ion to urea is impaired to varying degrees,
`and consequently
`its excretion is reduced. Ammonium is highly toxic
`to nerve cells and
`hyperammonaemia can damage the central nervous system leading to cerebral oedema and death.
`
`The elimination of nitrogen from the human body by a moiety other than urea was first proposed in
`1914, when Lewis described the stoichiometric relationship between the decrease in urine nitrogen as
`urea and the appearance of hippurate nitrogen in a normal subject given sodium benzoate.
`Subsequently, Sherwin in 1919 demonstrated the quantitative elimination of nitrogen in humans via
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`5/12
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`

`pheny lacety I glutamine following treatment with oral doses of phenylacetic acid (P A). The amino acid
`acylation products of sodium benzoate and sodium phenylacetate may substitute for urea nitrogen
`excretion in all UCD.
`
`The investigational use of P A for the treatment of patients with urea cycle disorders was started in
`clinical trials performed at Johns Hopkins University, USA, in 1980. Subsequently, the relevant
`permission was amended to include the investigational use of the combination of sodium benzoate and
`PA at several dosages. In 1983, a further amendment permitted the use of PB as a substitute for PA.
`Finally, in 1987, the use of PB only was introduced as a monotherapy replacing the combination
`therapy.
`
`The Office of Orphan Products Development supported the trial conducted with PB and the US
`Orphan status designation was granted on 22 November 1993. The results of this trial constitute the
`basis of the clinical part of the dossier. Although this trial does not comply with the requirements of
`Good Clinical Practice, it seems that the study population represents a significant proportion of
`patients with these rare disorders treated in the USA.
`Clinical pharmacology
`
`Pharmacodynamics - PB is a pro-drug, which is rapidly converted to P A by beta-oxidation in
`mammalian liver and kidneys. In higher primates, P A is enzymatically conjugated with glutamine in
`the liver and kidneys to form pheny lacety !glutamine (P AG), which is readily excreted in the urine.
`The glutamine required to excrete the P A will have to be synthesised and the reversible reaction:
`glutamine Bglutamic acid + NH4+ will proceed to the left and therefore ammonia will be excreted
`This cannot be demonstrated in animals due to species differences in the metabolic pathway of
`nitrogen elimination. On a molar basis, P AG is comparable to urea (each containing two nitrogen
`atoms) and provides an alternative vehicle for waste nitrogen disposal. Thus therapeutic administration
`of PB has the potential to divert nitrogen away from the blocked or impaired urea cycle and to provide
`an alternative pathway of excretion.
`
`Experimental support for the hypothesis outlined above is provided by the work of Prof. Brusilow's
`group at the Johns Hopkins school of Medicine. Brusilow demonstrated in 1991 in a child with
`carbamy 1 phosphate synthetase deficiency that administration of P A or PB resulted in the urinary
`excretion of P AG equivalent to 38-44% of the predicted normal nitrogen excretion. In other children
`with UCD, administration of PB or PA resulted in a decrease of 25-50% of baseline glutamine.
`Similar results were found in an adult male patient with ornithine transcarbamy lase deficiency, whose
`plasma ammonium and glutamine levels significantly declined with PB therapy.
`
`Pharmacokinetics - No formal pharmacokinetic studies have been performed with PB. Data from
`bioequivalence studies, and pilot studies in patients with cancer and haemoglobinopathies are cited.
`
`Studies in cancer patients have been performed where intravenous infusion of PB or P A has been used
`infusion, PB and PA display non-linear
`for anti-tumour activity. After
`intravenous bolus
`pharmacokinetics with a saturable elimination, which is consistent with an enzymatic process. During
`treatment with repeated doses of pheny lacetate there is evidence of an induction of drug clearance as
`shown by a significant decrease (27%) in the AUCs obtained at the beginning (days 1-3) compared
`with those in the end (days 12-14) of therapy, which the authors attribute to enzyme induction.
`Concentrations over 900 Jlg/ml were associated with sedation, confusion, nausea and vomiting.
`
`Pharmacokinetics after oral administration of PB have been studied in healthy volunteers (single dose
`of 2.5 g, n=2; single dose of 5 g, n= 21), in one patient with ornithine transcarbamylase deficiency and
`in 8 patients with haemoglobinopathies. PB is rapidly absorbed: measurable plasma levels of PB are
`detected 15 min after oral administration. Peak concentrations of approximately 1 mmol/1 are reached
`after 1 h. In one study, the elimination half-life was estimated to be 0.8 h. Measurable plasma levels of
`PA and PAG are detected 30-60 min after oral dosing ofPB (the mean peak concentration is 45.3 and
`62.8 Jlg/ml, respectively). The time to peak concentration increases with the dose of PB and is around
`3.5 h for both metabolites after a dose of 5 g of PB. The elimination half-life was estimated to be 1.3
`and 2.4 hours, respectively for P A and P AG. Recovery of PB and P AG from serial collections of urine
`has been evaluated in some of the cited studies. It is demonstrated that in most subjects, the kidneys
`within 24h excrete approximately 80-100% of the drug as the conjugated product, P AG. After oral
`administration, unchanged drug is not detected in the urine of normal subjects or patients with UCD. It
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`has not been determined if P A is secreted in human milk, therefore Ammonaps is contraindicated
`during breast-feeding.
`
`For all formulations used in the bioequivalence studies, the total exposure was greater in female than
`in male subjects, being about 20-25% and 40% higher for PB and PA, respectively. This gender
`difference has been mentioned in the SPC. This may be due to the lipophilicity of the drug and gender
`differences in volume of distribution. For PAG the difference was only about 10%. The principal
`indices of plasma pharmacokinetics of PB, P A and P AG in healthy male and female subjects are
`tabulated below (Table 1).
`
`Table 1 - Plasma pharmacokinetics (mean values) in healthy male (m) and female (f) subjects:
`
`tmax (h)
`M 1.18
`Pheny I butyrate
`F 1.21
`(PB)
`M3.62
`Pheny lacetate
`(PA)
`F 3.73
`M3.25
`Pheny lacety 1
`glutamine (P AG) F 3.43
`
`Cmax (J.lg/ml)
`M 192.5
`F 242.6
`M39.2
`F 55.1
`M 67.4
`F 66.9
`
`AUC (J.lg·h/ml)
`M 480.1
`F 622.1
`M 154.4
`F 245.8
`M 282.7
`F 297.7
`
`tvz (h)
`M0.78
`F 0.82
`M 1.2
`F 1.26
`M2.12
`F 2.66
`
`Bioequivalence studies - In a single dose three-way crossover study, healthy male (n=lO) and female
`(n= ll) volunteers received a) PB 500 mg tablets, American Drug Development Inc., b) PB powder,
`Pharmaceutical services University of Iowa or c) PB 500 mg tablets, Pharmaceutical Services
`University of Iowa. In all cases the dose was 5 grams. A and B were considered the test and C the
`reference formulations. Results are tabulated below (Table 2) and indicate that the bioavailability of
`the powder formulation is less than that of the tablets, but remains within the usual regulatory criterion
`of ± 20%.
`
`Table 2 - Relative bioavailability (mean values) of test tablets (a) and powder (b) compared to
`reference tablets (c):
`
`Pheny I butyrate
`(PB)
`
`tmax (h)
`a) 1.4
`b) 1.0
`c) 1.2
`d) 3.7
`e) 3.6
`f) 3.7
`g) 3.4
`Pheny lacety 1
`glutamine (P AG) h) 3.2
`i) 3.4
`
`Pheny lacetate
`(PA)
`
`Cmax (J.lg/ml)
`a) 218
`b) 195
`c) 240
`d) 49
`e) 45
`f) 54
`g) 69
`h) 63
`i) 69
`
`AUC (J.lg·h/ml)
`a) 577
`b) 494
`c) 586
`d) 211
`e) 188
`f) 231
`g) 306
`h) 268
`i) 301
`
`tvz (h)
`a) 0.77
`b) 0.76
`c) 0.85
`d) 1.15
`e) 1.29
`f) 1.25
`g) 2.41
`h) 2.36
`i) 2.56
`
`All formulations in the bioequivalence study contained approximately the same amount of active
`substance and relatively minor differences in excipients. No safety problems have been observed from
`clinical experience with the proposed commercial formulation, as distinct from development
`formulations .
`
`Interaction studies -No studies of drug interactions are included in support of the application. There
`have been publications reporting that: renal excretion of the PB conjugation product may be affected
`by concurrent administration of probenecid; hyperammonia may be induced by haloperidol and by
`valproate; corticosteroid may cause increase in plasma ammmonia levels. More frequent monitoring of
`plasma ammonia levels is advised in the SPC when using these medications.
`
`There is no formal food interaction study available. The suggestion for administration with food is
`based on experience gained in clinical practice. In addition, the dose is to be titrated against metabolic
`states and an important principle would seem to be that the administration with or without is kept
`constant.
`
`Special patient groups - The pharmacokinetics of PB have been studied in male patients with hepatic
`cirrhosis (oral administration, 20 g/day in three doses). Plasma levels of PB followed the peak and
`
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`

`trough pattern familiar from healthy subjects and UCD patients. The conversion of P A to P AG was
`relatively slower in these patients with impaired hepatic function as evidenced by progressive
`accumulation of P A in the plasma of 3 out of the 6 patients studied; this pattern is not found in
`subjects with normal liver function. In addition, PB and P A were detected in urine. This suggests that
`in patients with cirrhosis the capacity of the metabolic pathway of P A is reduced.
`
`The pharmacokinetics of PB have not been studied in patients with renal impairment.
`
`Appropriate information concerning these high risk groups is contained in the SPC.
`
`Dosage -No formal dose finding study has been performed. The proposed daily dosage was derived
`on the basis that one mole of PB will be metabolised to one mole of P AG, and from the estimated
`nitrogen to be excreted on a restricted intake. Excretion of 0.09 g/kg/d of PAG nitrogen would require
`a dose of 0.6 g/kg/d of PB. It is likely that the efficiency of excretion varies between patients and
`individual titration is recommended on the basis of therapeutic monitoring. Based on this reasoning,
`the following regimen is proposed:
`
`450 - 600 mg/kg/day in neonates, infants and children weighing less than 20 kg
`9.9- 13.0 g/m2/day in children weighing more than 20 kg, adolescents and adults.
`
`Clinical efficacy
`
`The most important efficacy data are derived from the Phase III clinical trial, based on the US(cid:173)
`IND/NDA program. In this study, patients with UCDs [deficiency of carbamyl phosphate synthetase
`(CPS), ornithine transcarbamylase (OTC) or argininosuccinate synthetase (ASS)] were enrolled in an
`open, non-comparative multicentre study. The first patient was enrolled in 1985 and the cut-off for
`data analysis was February 1996. The IND program consisted of two cohorts of data, as outlined
`below.
`
`Study population - The first treatment program (1985-1994) consists of 162 patients, of which 148
`were evaluable (87 with prior therapy and 61 without prior therapy). The following UCDs had been
`diagn