Profile of sodium phenylbutyrate granules for the treatment of urea-cycle disorders: Patient perspectives

© 2017 Peña-Quin ana e al. This wo k is published and licensed by Do e Medical P ess Limi ed. The ull e ms o his license a e a ailable a h ps://www.do ep ess.com/ e ms.php and inco po a e he C ea i e Commons A ibu ion – Non Comme cial (unpo ed, 3.0) License (h p://c ea i ecommons.o g/licenses/by-nc/3.0/). By accessing he wo k you he eby accep he Te ms. Non-comme cial uses o he wo k a e pe mi ed wi hou any u he pe mission om Do e Medical P ess Limi ed, p o ided he wo k is p ope ly a ibu ed. Fo pe mission o comme cial use o his wo k, please see pa ag aphs 4.2 and 5 o ou Te ms (h ps://www.do ep ess.com/ e ms.php). Pa ien P e e ence and Adhe ence 2017:11 1489–1496 Pa ien P e e ence and Adhe ence Do ep ess submi you manusc ip | www.do ep ess.com Do ep ess 1489 Re iew open access o scien i ic and medical esea ch Open Access Full Tex A icle h p://dx.doi.o g/10.2147/PPA.S136754 P o ile o sodium phenylbu y a e g anules o he ea men o u ea-cycle diso de s: pa ien pe spec i es Luis Peña-Quin ana1–3 Ma a Lla ena2 Deside io Reyes-Suá ez2 Luis Aldámiz-Eche a ia4 1Pedia ic Gas oen e ology, Hepa ology, and Nu i ion Uni , Uni e si a io Ma e no-In an il Hospi al de Cana ias, Uni e si y o Las Palmas de G an Cana ia, 2Resea ch ins i u e o Biomedical and Heal h Sciences, Uni e si y o Las Palmas de G an Cana ia, Las Palmas, 3CIBEROBN, Mad id, 4Uni o Me abolism, C uces Uni e si y Hospi al, BioC uces Heal h Resea ch Ins i u e, GCV-CIBER de En emedades Ra as (CIBERER), Ba akaldo, Spain Abs ac : U ea-cycle diso de s a e a g oup o a e he edi a y me abolic diseases cha ac e ized by de iciencies o one o he enzymes and anspo e s in ol ed in he u ea cycle, which is neces- sa y o he emo al o ni ogen p oduced om p o ein b eakdown. These he edi a y me abolic diseases a e cha ac e ized by hype ammonemia and li e- h ea ening hype ammonemic c ises. Pha macological ea men o u ea-cycle diso de s in ol es al e na i e ni ogen-sca enging pa hways. Sodium benzoa e combines wi h glycine and phenylace a e/phenylbu y a e wi h glu amine, o ming, espec i ely, hippu ic acid and phenylace ylglu amine, which a e elimina ed in he u ine. Among he ammonia-sca enging d ugs, sodium phenylbu y a e is a well-known long- e m ea men o u ea-cycle diso de s. I has been used since 1987 as an in es iga ional new d ug, and was app o ed o ma ke ing in he US in 1996 and he EU in 1999. Howe e , sodium phenylbu y a e has an a e si e odo and as e, which may comp omise pa ien s’ compliance, and many pa ien s ha e epo ed di icul y in aking his d ug. Sodium phenylbu y a e g anules a e a new as eless and odo - ee o mula ion o sodium phenylbu y a e, which is indica ed in he ea men o u ea-cycle diso de s. This ecen ly de eloped as e-masked o mula ion o sodium phenylbu y a e g anules was designed o o e come he conside able issues ha as e has on adhe - ence o he apy. Se e al s udies ha e epo ed he clinical expe ience o pa ien s wi h u ea-cycle diso de s ea ed wi h his new as eless o mula ion o sodium phenylbu y a e. Analysis o he da a indica ed ha his as e-masked o mula ion o sodium phenylbu y a e g anules imp o ed quali y o li e o u ea-cycle diso de pa ien s. Fu he mo e, a pos ma ke ing epo on he use o he p oduc has con i med he p e ious obse a ions o imp o ed compliance, e icacy, and sa e y wi h his as e-masked o mula ion o sodium phenylbu y a e. Keywo ds: sodium phenylbu y a e g anules, u ea-cycle diso de s, ea men adhe ence, quali y o li e U ea-cycle diso de s U ea-cycle diso de s (UCDs) a e a g oup o a e he edi a y me abolic diseases cha ac e ized by de iciencies o one o he enzymes and anspo e s in ol ed in he UC. Six diso de s in ol ing di e en de ec s in he biosyn hesis o hese enzymes ha e been desc ibed: CPS1 de iciency1 (MIM 237300), NAGS de iciency (MIM 237310), OTC de iciency2 (MIM 311250), ASS1 de iciency,3 ci ullinemia ype I (MIM 215700), ASL de iciency4 (MIM 207900), and ARG1 de iciency5 (MIM 207800). Excep o OTC de iciency, which is X-linked, hese diso de s display an au osomal- ecessi e inhe i ance.6 Addi ionally, he e a e h ee anspo e de ec s: mi ochond ial o ni hine ca ie (hype o ni hinemia–hype ammonemia–homoci ullinu ia synd ome; MIM 238970), mi ochond ial aspa a e–glu ama e ca ie (ci ullinemia ype II; MIM 605814, Co espondence: Luis Peña-Quin ana Pedia ic Gas oen e ology, Hepa ology, and Nu i ion Uni , Uni e si a io Ma e no-In an il Hospi al o Cana ias, Uni e si y o Las Palmas de G an Cana ia, A enida Ma í ima del Su , Las Palmas, G an Cana ia 35016, Spain Tel +34 928 308 645 Fax +34 928 308 780 email [email p o ec ed]s Jou nal name: Pa ien P e e ence and Adhe ence A icle Designa ion: Re iew Yea : 2017 Volume: 11 Running head e so: Peña-Quin ana e al Running head ec o: Sodium phenylbu y a e g anules o u ea-cycle diso de s DOI: 136754 Pa ien P e e ence and Adhe ence downloaded om h ps://www.do ep ess.com/ by 193.145.136.228 on 20-Oc -2017 Fo pe sonal use only. Powe ed by TCPDF (www. cpd .o g) 1 / 1 Numbe o imes his a icle has been iewed This a icle was published in he ollowing Do e P ess jou nal: Pa ien P e e ence and Adhe ence 6 Sep embe 2017 Pa ien P e e ence and Adhe ence 2017:11 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess 1490 Peña-Quin ana e al 603471), and dibasic amino-acid ca ie (hype dibasic amino- acidu ia o lysinu ic p o ein in ole ance; MIM 222700).6 The incidence o UCDs is es ima ed o 1:8,000–1:44,000 bi hs.7,8 Howe e , hese numbe s may unde es ima e p e alence, due o un eliable newbo n-sc eening p og ams and unde diag- nosis o hese diso de s in a al cases. Clinical symp oms UCDs may p esen du ing he neona al pe iod, a e a a iable symp om- ee in e al. In hese cases, hey a e cha ac e ized by o e whelming illness, which apidly p og esses om poo eeding, omi ing, le ha gy, and/o i i abili y o coma and/o dea h.9–14 Howe e , mos o hese diso de s usually display a la e-onse o m (childhood and/o adul hood), which is caused by pa ial enzyma ic ac i i y de iciencies. Thei symp oms, which a e less se e e and mo e a iable, include poo de elopmen al p og ess, beha io al p oblems, hepa omegaly, and gas oin es inal diso de s. In pa ien s wi h UCDs, acu e episodes o hype ammonemia a e ecu en and can be igge ed by me abolic s ess in esponse o in ec ion, auma, su ge y, o p egnancy.9–14 In addi ion, pa ien s wi h UCDs o en p esen ch onic neu ological illness. In his ega d, hype ammonemia- ela ed neu ologic inju y anges om le hal ce eb al edema o mild o subclinical cogni i e impai men among indi iduals wi h milde pheno ypes. Fu he mo e, abno mali ies in execu i e unc ion, mani es ed by di icul y in goal se ing, planning, moni o ing p og ess, and pu pose ul p oblem sol ing signi ican ly impai day- o- day unc ion among child en wi h UCDs, e en hose wi h milde disease who p esen beyond he neona al pe iod.15 The pa hogenesis o hype ammonemia in UCDs is p oduced in pa by al e ed ammonia de oxi ica ion o u ea and in pa by enhanced ca abolism o glu amine, mos ly in skele al muscle, bu also o a lesse deg ee in he b ain and likely in he lungs. The majo i y o glu amine eleased in o ci cula ion is ca abolized back in o ammonia in en e ocy es and he kidneys.16 Managemen and ea men Timely diagnosis and p omp ea men a e c ucial o he managemen o UCDs. The absence o e ec i e ea ly ea - men esul s in ammonia accumula ion, which leads o i e- e sible b ain damage. The main goal in he managemen o pa ien s wi h UCD is o achie e good me abolic con ol o he disease, while ensu ing ha nu i ional equi emen s a e me . The e o e, he long- e m ea men o pa ien s wi h UCDs is based on die a y p o ein es ic ion and die a y supple- men s ha consis o all essen ial amino acids, i amins, and mine als.17 This he apy is complemen ed wi h he use o ammonia-sca enging d ugs, such as benzoa e and pheny- lace a e (PA)/phenylbu y a e (PB). These d ugs p e en he accumula ion o ammonia p o iding an al e na i e pa hway o ni ogen disposal h ough he combina ion wi h glycine in he case o benzoa e and glu amine o PA/PB, o ming hippu ic acid and phenylace ylglu amine, espec i ely. Fo each mole o benzoa e and PA/PB, 1 and 2 mol o ammonia a e elimina ed easily in he u ine. On he o he hand, he UC could be elie ed by di e ing i s subs a es. By his way o a oiding he UC, u ea syn hesis is enhanced, in o de o suppo ni ogen homeos asis u he .7,18,19 Figu e 1 shows he mechanism by which PA/PB dec eases ammonia. In addi- ion, pa ien s o all ages wi h NAGS de iciency a e ea ed wi h ca glumic acid, which is a syn he ic o m o NAG. This chemical compound ac s as a eplacemen o he co ac o Figu e 1 Al e na i e ou e o ammonia emo al by phenylace a e/phenylbu y a e ac ion on glu amine. $ODQLQH JO FLQH *OXWDPLQH *OXWDPDWH %HQ]RDWH 3KHQ OEXW UDWH 3KHQ ODFHWDWH 1+  $VSDUWDWH 3KHQ ODFHW O JOXWDPLQH +LSSXUDWH 8ULQH Pa ien P e e ence and Adhe ence downloaded om h ps://www.do ep ess.com/ by 193.145.136.228 on 20-Oc -2017 Fo pe sonal use only. Powe ed by TCPDF (www. cpd .o g) 1 / 1 Pa ien P e e ence and Adhe ence 2017:11 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess 1491 Sodium phenylbu y a e g anules o u ea-cycle diso de s NAG, which is he key o s a ing he UC and hus he p ocess o emo ing excess ammonia.20 Ammonia-sca enging d ugs As men ioned, dis up ions o ni ogen homeos asis lead o an excessi e and noxious accumula ion o ammonia. I is well known ha ele a ed ammonia le els (.100 μmol/L) a e ex emely oxic o he cen al ne ous sys em. Indeed, pa ien p ognosis is conside ed o be e y poo when a hype - ammonemic coma has las ed mo e han 3 days, in ac anial p essu e is ma kedly ele a ed, o when ammonia le els a e .1,000 μmol/L.21,22 Fo his eason, he use o d ugs ha a e able o lowe ammonia le els and ac as ammonia sca enge s a e included in he he apeu ic egimens o acu e and ch onic ea men o UCDs (Table 1). Benzoa e was he i s -desc ibed ammonia-sca enging d ug. I s use was p oposed in 1914.23 Based on p e iously published s udies, sodium benzoa e was adminis e ed as a supplemen o 26 child en wi h de ec i e u eagenic pa h- ways. The esul s indica ed ha benzoa e could be used o con ol de ec s in ni ogen exc e ion.24 Mo eo e , he same au ho s also showed ha sodium PA supplemen a ion caused ammonia elimina ion by i s conjuga ion o glu amine and phe- nylace ylglu amine exc e ion in pa ien s wi h UCDs.25 These s udies led o he app o al in he ea ly 1980s by he US Food and D ug Adminis a ion (FDA) o combined he apy wi h sodium benzoa e and sodium PA o ea hype ammonemia in UCDs. In 2005, an in a enous combina ion o sodium PA and sodium benzoa e (Ammonul; Valean Pha maceu icals No h Ame ica LLC, B idgewa e , NJ, USA) was app o ed by he FDA.26 One e y signi ican d awback o PA he apy was he aw ul odo caused by any spilled medicine and by he swea and u ine o he pa ien s. To o e come his disad an- age, he use o PB, which is a me abolic p ecu so o PA wi h a less disag eeable odo , was p oposed. The e o e, in 1983, a u he amendmen pe mi ed he eplacemen o PA by PB. In 1987, he i s PB-de i a i e sal (sodium PB [NaPB]) was in oduced expe imen ally as a new in es iga ional d ug. Finally, he use o NaPB o eplace he combined he apy25 was app o ed as a sa e, well- ole a ed mono he apy o phan d ug o he ea men o UCDs.27 The e o e, he ma ke ing o NaPB (Ammonaps and Buphenyl) o UCD was app o ed in he US by he FDA in 1996 and in Eu ope by he Eu opean Medicines Agency (EMA) in 1999.28 In addi ion, he e has been a ecen ly de eloped as e-masked o mula ion o NaPB g anules (Phebu ane)29 o o e come he conside able issues ha as e has on adhe ence o he apy. Fu he mo e, he e a e o he in es iga ional agen s being de eloped o he ea - men o UCDs, such as glyce ol PB (HPN-100; Hype ion The apeu ics, San F ancisco, CA, USA).30,31 Common ad e se e ec s o ammonia-sca enging d ugs Commonly epo ed ad e se e ec s o combined he apy wi h sodium benzoa e–sodium PA include diso de s a ec ing he espi a o y, blood, lympha ic, and ne ous sys ems o me abolism and nu i ion and omi ing.26 Wi h ega d o PA/PB adminis a ion, al hough i is well ole a ed in mos cases, hepa o oxici y side e ec s associa ed wi h in e ac- ions be ween hese d ugs and li e cy och ome P450 ha e been desc ibed.32 Fu he mo e, i should be men ioned ha PA/PB ac s as a his one deace ylase inhibi o and has been in es iga ed o use in he ea men o a numbe o malig- nan diso de s. The e o e, PA/PB adminis a ion may cause se ious ad e se e ec s, eg, li e inju y.33,34 Le els o glu amine in he blood and a ious issues in UCDs a e gene ally ele a ed. PA/PB he apy can induce deple ion o glu amine, so i s le els should be moni o ed Table 1 Summa y o a ailable ea men s o u ea-cycle diso de s Ac i e p incipal B and/manu ac u e Adminis a ion/dosage Disad an ages Ad an ages Re e ences Sodium benzoa e Pha ma in e na ional O al, 500 mg able Poo adhe ence 7 Sodium benzoa e Pha ma in e na ional O al, 100 mg/mL Poo adhe ence Adap ed o child en 7 Sodium benzoa e Pha ma in e na ional IV, 2 g/10 mL Independen dosing 7 Sodium benzoa e and sodium PB Ammonul ( alean Pha maceu icals) IV, 10% and 10% 26 Sodium PB Pha ma in e na ional IV, 2 g/10 mL Independen dosing 7 Sodium PB Ammonaps (Swedish O phan Bio i um) O al, 500 mg able Poo adhe ence Adap ed o child en 39 Sodium PB Buphenyl (Ho izon Pha ma) O al, 250 mg able Poo adhe ence Adap ed o child en 7 Sodium PB Buphenyl (Ho izon Pha ma) Powde , 3.2 g/3 g Poo adhe ence Adap ed o child en 7 Sodium PB Phebu ane (Lucane Pha ma) G anules No la o Needs collabo a ion by pa ien 29, 44 Glyce ol PB Ra ic i (Ho izon Pha ma) 1 mg/mL No la o Adap ed o all ages 48 Abb e ia ions: IV, in a enous; PB, phenylbu y a e. Pa ien P e e ence and Adhe ence downloaded om h ps://www.do ep ess.com/ by 193.145.136.228 on 20-Oc -2017 Fo pe sonal use only. Powe ed by TCPDF (www. cpd .o g) 1 / 1 Pa ien P e e ence and Adhe ence 2017:11 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess 1492 Peña-Quin ana e al egula ly. Good con ol is conside ed o be 800–1,000 μmol/L o glu amine in he blood. Glu amine deple ion may ac i a e b anched-chain amino acid (BCAA) ca abolism and cause deple ion o BCAAs,35–37 which may inc ease he isk o endogenous p o ein ca abolism,38 sugges ing a po en ial need o BCAA supplemen a ion o PA/PB he apy. The main sou ce o amino ni ogen o syn hesis o glu ama e (p ecu so o glu amine) is BCAAs.16 On he o he hand, glu amine deple ion may exe ad e se e ec s on he body, such as impai ed immuno esponse and gu in eg i y.16 NaPB ep esen s an imp o emen on PA he apy o UCDs. Howe e , i s ill equi es he inges ion o up o 40 la ge capsules a day, has a disag eeable as e, and sickens some indi iduals. Indeed, as e dis u bance and omi ing ha e been epo ed as “ equen ” unpleasan ad e se e en s associa ed wi h he d ug’s o al inges ion in he summa y o p oduc cha ac e is ics o NaPB (Ammonaps).39 Mo eo e , dysgeusia/ageusia can also comp omise he la o o ood, which is an addi ional p oblem in a pa ien wi h UCD, whose eeding is al eady e y di icul due o die a y es ic ions and need o supplemen a ion. In ac , his adds a signi ican bu den o he s ess o amilies, who a e aced wi h he daily challenge o ge ing hei child en o ake medicine o his li e- h ea ening disease.40 This well-known no o iously a e - si e as e o NaPB40 has been con i med by elec onic ongue and eal- ime dissolu ion in i o s udies, as well as by s ud- ies in heal hy olun ee s.41 Due o he unaccep abili y o he NaPB o mula ion(s) on he ma ke , some pa ien s can ei he no ake he d ug (e en i e o mula ed) o change i s admin- is a ion, eg, ia nasogas ic ubing o gas o omy. The e a e common p ac ical a emp s used by pa en s and medical s a o dilu e he d ug o y o obscu e i s as e by mixing o sp inkling i wi h oods o d inks. Howe e , hese app oaches may lead o impai ed e icacy, due o incomple e d ug dosing i he mix u e is no ully consumed, and may also cause he child o de elop a e sion o he oods used in he masking p ocess. As a consequence, he e is an ine ec i eness o he ea men ha can lead o i e e sible b ain damage seconda y o hype ammonemia. In his line o esea ch, se e al s udies ha e shown ha a he ecommended doses o he ea men o UCDs (250–500 mg/kg/day, maximum 12 g/day), NaPB dec eases appe i e, dis u bs as e, and causes disag eeable body odo in app oxima ely 5% o pa ien s.28,40 Fu he mo e, ch onic ea men wi h PB causes mens ual dys unc ion/ ameno hea in abou 25% o pos pube al emales.28 Sodium phenylbu y a e g anules As men ioned, die a y es ic ion combined wi h NaPB is one o he main he apeu ic modali ies used in ch onic ea men o UCDs, and has been a ailable o o e h ee decades.25 Due o he pala abili y issues associa ed wi h NaPB, he e has been ecen in e es in he de elopmen o new o mula ions o his d ug o o e come he se ious issue o i s oul, bi e as e, which may a ec pa ien adhe ence o he ea men . O e he yea s, a emp s o mask his bi e and ex emely unpleasan as e in ood and d ink ha e ailed, causing hese child en o be unde ea ed, wi h esul an poo me abolic con ol. The de elopmen o a as e-masked g anule o mula ion o NaPB ha can be swallowed be o e as e ecep o s a e s imula ed is an example o a he apeu ic ic o y achie ed h ough echnological solu ions.41,42 NaPB g anules (Phebu ane) a e a new as e-masked and odo - ee o mula ion o NaPB ha has been de eloped by Lucane Pha ma (Pa is, F ance).29 NaPB g anules a e small sphe ical suga co es coa ed wi h NaPB and e hyl cellulose in wo sepa- a e laye s. E hyl cellulose is a well-known as e-masking agen o ac i e subs ances.41 This as e-masked g anule o mula ion o NaPB begins o elease NaPB a e a lag o app oxima ely 10 seconds, ollowed by slow elease o e se e al minu es.29 In con as , he ma ke -licensed NaPB eleases he ac i e d ug ully and immedia ely, leading o immedia e elease o he oul as e. As such, he as e-masked g anule o mula ion o NaPB c ea es a window o oppo uni y o swallow he o mula ion comple ely be o e i s as e and odo become appa en . The p o ile o NaPB g anules has been desc ibed in de ail by he EMA.29 This documen p o ides a ull desc ip ion o se e al aspec s o his d ug, including he apeu ic indica ions, posology, me hod o adminis a ion, con aindica ions, and special wa nings/p ecau ions o use. In addi ion, i includes he sa e y p o ile o NaPB g anules wi h a abula ed lis o epo ed ad e se eac ions by sys em-o gan class and equency. In clinical ials wi h NaPB, 56% o he pa ien s expe ienced a leas one ad e se e en , and 78% o hese we e conside ed no ela ed o NaPB. Ad e se eac ions mainly in ol ed he ep oduc i e and gas oin es inal sys em.29 The ollowing common ad e se eac ions we e epo ed: blood and lympha ic sys em diso de s (anemia, h ombocy openia, leukopenia, leukocy osis, h ombocy osis), me abolism and nu i ion diso de s (me abolic acidosis, alkalosis, dec eased appe i e), gas oin es inal diso de s (abdominal pain, omi - ing, nausea, cons ipa ion, dysgeusia), skin and subcu aneous issue diso de s ( ash, abno mal skin odo ), and enal and u ina y diso de s ( enal ubula acidosis).29 F om in es iga- ions, dec eased blood po assium, albumin, o al p o ein, and phospha e and inc eased blood alkaline phospha ase, ansam- inases, bili ubin, u ic acid, chlo ide, phospha e, sodium, and weigh we e epo ed.29 The EMA p o ile also includes he Pa ien P e e ence and Adhe ence downloaded om h ps://www.do ep ess.com/ by 193.145.136.228 on 20-Oc -2017 Fo pe sonal use only. Powe ed by TCPDF (www. cpd .o g) 1 / 1 Pa ien P e e ence and Adhe ence 2017:11 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess 1493 Sodium phenylbu y a e g anules o u ea-cycle diso de s pha macological (pha macodynamic and pha macokine ic) p ope ies o NaPB g anules.29 I should be poin ed ou ha NaPB g anules should be adminis e ed o ally; he e o e, adminis a ion equi es he coope a ion o he pa ien .29 To da e, wo clinical ials ha e shown he esul s o he use o as e-masked NaPB g anules in pa ien s wi h UCD unde a F ench-coho empo a y u iliza ion au ho iza ion (ATU) p o ocol.43,44 In Sep embe 2012, he F ench medicines agency g an ed a coho -ATU p o ocol o NaPB g anules, allowing i s use in UCD pa ien s no able o ole a e he ma ke ed p oduc due o i s unpala abili y. NaPB g anules we e g an ed ma ke au ho iza ion in he EU on July 31, 2013, and hus he las da e o inclusion in he coho -ATU p o ocol was Oc obe 31, 2013. In 2014, Kibleu e al published he esul s o he i s F ench na ionwide 1-yea coho s udy on 25 pa ien s, o whom 21 we e child en.43 The aim o his s udy was o desc ibe a na ionwide sys em o p ema ke ing ollow-up o NaPB g anules in F ance and o analyze sa e y and e icacy in his coho o pa ien s ea ed wi h UCDs. Mos pa ien s joined he s udy due o majo issues wi h he as e o he ma ke ed o mula ions o NaPB, as indica ed by he esul s om pa ien s’ su eys o assessmen o pala - abili y and ease o di icul y o adminis a ion o he a ailable ma ke ed d ug. A e jus one dose o NaPB g anules, as e and global accep abili y e alua ions indica ed a d ama ic inc ease in accep abili y, a dec ease in pe cei ed bi e ness, and an in e se co ela ion be ween gene al accep abili y and bi e ness compa ed wi h a e one dose o he licensed ma ke ed p oduc .43 In addi ion, no pa ien in he ATU p o ocol epo ed any ad e se e en ela ed o omi ing ol- lowing adminis a ion o NaPB g anules compa ed o when ecei ing ma ke ed NaPB p io o en y in o he coho -ATU p o ocol.43 The absence o such omi ing e lex ollowing d ug in ake wi h NaPB g anules ob ia es he need o edos- ing and hus he isk o o e dose o he isk o unde dosing in hose cases when he dose was no adequa ely eadminis e ed. Mo eo e , no addi ional measu e, such as e o mula ion in o capsules, was equi ed o adminis e NaPB g anules, which we e aken o ally in all pa ien s in he ATU ollow-up.43 This ep esen s a d ama ic imp o emen in ca e o hese pa ien s. The mos impo an clinical ou come was he change in episodes o hype ammonemia. In he coho -ATU p o ocol, he numbe o hype ammonemic episodes dec eased om 20, as epo ed in en licensed NaPB- ea ed pa ien s in he p e ious 6 mon hs, o 0 in he same pa ien s ea ed wi h NaPB g anules o e a pe iod o 3–11 mon hs.43 Al hough he coho -ATU p o ocol was no designed o collec any measu emen o compliance o quali y o li e (QoL), analysis o he da a indica ed ha he QoL o UCD pa ien s and hei amilies imp o ed g ea ly wi h NaPB g anules, as assessed on ease o adminis a ion and meaning ully educed inci- dence o ad e se e en s, no ably omi ing and dysgeusia, which impai pa ien s’ well-being and/o hei accep ance/ compliance wi h pha maceu ical ea men s.43 In Janua y 2016, Kibleu and Gu on epo ed he esul s o u he ollow-up o pa o he o iginal ATU-coho p o ocol.44 The aim o his s udy was o desc ibe he s a us o pa ien s wi h UCDs a he la es long- e m clinical ollow-up o ea men wi h NaPB g anules. Pa ien s om he o iginal ATU coho we e ollowed up e e y 6–12 mon hs a one e e ence cen e . Long- e m ollow-up da a suppo ed he p e iously obse ed imp o emen s in d ug ole abili y.43 Mo eo e , ollow-up da a also con i med he p o ec i e e ec o NaPB g anules agains me abolic decompensa ions. Indeed, in he long e m, imp o ed biochemical con ol, as assessed by an absence o episodes o clinical decompensa- ion, educ ion in plasma ammonia and glu amine le els, and imp o ed neu ocogni i e and heigh :weigh s a us, we e obse ed in he g oup o pa ien s ea ed wi h NaPB g anules.44 This obse ed imp o ed clinical s a us a e long- e m adminis a ion o NaPB g anules may e lec e icacy and imp o ed compliance wi h his as eless o mula ion o NaPB, as well as indica ing an imp o emen in pa ien s’ and hei amilies’ QoL, as expec ed wi h as eless p oduc s.31,45 I is wo h men ioning ha he sa e y o NaPB g anules was also con i med om expe ience in o he pa ien s in Sweden and in Tu key who ecei ed he d ug unde a named pa ien p og am p io o ma ke ing app o al.43,46 In 2015, Uça e al epo ed on 1-yea usage o NaPB g anules in a case o la e-onse ASL de iciency on a named pa ien p og am in Tu key.46 The amily epo ed he child’s e usal o ea o d ink due o he as e and smell o NaPB, as well as hei unsuccess ul a emp s o mask he as e o he d ug in ood. The consequences o he child no aking he medica ion added a signi ican bu den o he s ess al eady expe ienced by he pa en s, as indica ed by hei QoL sco e. Fo hese easons, he as eless and odo - ee o mula ion NaPB g anules was p esc ibed. A e 1 mon h o ea men , he pa ien became ully complian wi h he d ug. In addi- ion, no hype ammonemia episodes occu ed o e 1 yea o ea men . Mo eo e , a dec ease in amily s ess and anxie y was obse ed, wi h QoL measu emen indica ing a signi i- can imp o emen .46 O he u u e al e na i es: glyce ol phenylbu y a e In ecen yea s, g ea e o has gone in o de eloping new de i a i es o ammonia-sca enging d ugs wi h ewe ad e se Pa ien P e e ence and Adhe ence downloaded om h ps://www.do ep ess.com/ by 193.145.136.228 on 20-Oc -2017 Fo pe sonal use only. Powe ed by TCPDF (www. cpd .o g) 1 / 1 Pa ien P e e ence and Adhe ence 2017:11 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess 1494 Peña-Quin ana e al e ec s, such as pala abili y issues, in ake o high numbe s o capsules, o high sodium con en . I should be poin ed ou ha he maximum app o ed daily dose o NaPB (20 g) con ains app oxima ely 2,400 mg o sodium, which exceeds he daily allowance o 2,300 mg/day o he gene al popula- ion and 1,500 mg/day o indi iduals wi h hype ension and ce ain o he sodium- e aining s a es, as ecommended by he US Depa men o Heal h and Human Se ices in he 2005 Die a y Guidelines o Ame icans.47 In his line o esea ch, he use o he glyce ol PB, which consis s o h ee molecules o PB and a glyce ol backbone, has been ecommended as an op ion o eplace NaPB. In ac , glyce ol PB (HPN-100; Hype ion The apeu ics) has been app o ed o ea men o UCD. Glyce ol PB was shown o be a mo e ole able when adminis e ed o pa ien s han NaPB, since his d ug has he ad an age o being a ailable as a as eless, odo less liquid ha can be gi en in doses o a ew easpoons a day. Mo eo e , i s pha macokine ic p ope - ies a e cha ac e ized by slowe , mo e e ec i e elease o he ac i e me aboli e (PA) when compa ed wi h he unconjuga ed PB. In his ega d, Lee e al demons a ed ha glyce ol PB was as e ec i e as NaPB in deli e ing PB o he body.30 Fu he mo e, se e al clinical ials ha e shown ha glyce ol PB was e ec i e in main aining ammonia le els in a desi - able ange, and he a e o hype ammonemia episodes and associa ed complica ions we e educed. In pa icula , he conclusions om a pi o al Phase III s udy o glyce ol PB o UCD and om sho - and long- e m ammonia-con ol and neu ocogni i e ou comes om 91 UCD pa ien s in ou clinical ials showed ha glyce ol PB exhibi ed a o able pha macokine ics and ammonia con ol ela i e o NaPB, and ha long- e m glyce ol PB ea men in pedia ic pa ien s was associa ed wi h imp o ed execu i e unc ion.31 Finally, i has been demons a ed ha glyce ol PB is well ole a ed and has ewe gas oin es inal complica ions han sodium benzoa e o NaPB ea men .48 Conclusion Fo o e 40 yea s, ammonia-sca enging d ugs ha e been used in he ea men o UCDs. Benzoa e, PA/PB, and NaPB a ge li e -ni ogen me abolism by o e ing an al e na i e pa hway o ni ogen disposal h ough he u ina y exc e ion o hippu a e and phenylace ylglu amine. Thei sa e y and e icacy in he ea men o UCDs is well es ablished,18 and hey a e usually well ole a ed among pa ien s. Howe e , in ecen yea s he iden i ica ion o no el ammonia-sca enging de i a i es, which display imp o ed ac ions and exhibi ewe o e all ad e se e ec s, has been a ho opic in esea ch. I is well known ha due o NaPB’s unpleasan as e and odo , many pa ien s wi h UCDs ha e epo ed ha hey could no ake he d ug. As such, pa ien s’ nonaccep ance o he ma ke ed NaPB p oduc led o he op imiza ion and de elopmen o no el pha macological de i a i es o his d ug, such as NaPB g anules (Phebu ane), o o he new de i a i es wi h dis inc pha macological cha ac e is ics, such as glyce ol PB.30 Wi h his e iew, we ha e sha ed epo ed expe ience in he use o NaPB g anules wi h he aim o in o ming clinicians abou his new op ion o ea men in UCDs.43,44,46 Fi s ly, he new g anule o mula ion o NaPB has been shown o be e ec i ely as e-masked.41,42 Indeed, acco ding o pa ien su eys, as e and global accep abili y a e imp o ed. Secondly, dysgeusia o omi ing was no epo ed by pa ien s ollowing NaPB-g anule in ake compa ed o ma ke ed NaPB o mula ions. The e o e, ewe ad e se e ec s due o o e /unde dosing migh be expec ed wi h NaPB g anules. Thi dly, and p obably he mos impo an clinical ou come, a dec ease in episodes o hype ammonemia was obse ed in a coho o NaPB g anule- ea ed pa ien s. Finally, his as e-masked o mula ion o NaPB also imp o ed compliance in ea men and QoL o UCD pa ien s and hei amilies. Finally, conside ing ha new aspec s o NaPB usage a e eme ging ha may indica e u he he apeu ic ac i i y, he de elopmen o a new NaPB o mula ion ha is a mo e pala able is ex emely impo an . In his ega d, i has been shown ha PB enhances py u a e dehyd ogenase-complex enzyma ic ac i i y in i o and in i o by inc easing he p opo ion o unphospho yla ed enzymes h ough inhibi ion o py u a e dehyd ogenase kinase. These indings sugges he po en ial use o PB o ea men o pa ien s wi h py u- a e dehyd ogenase-complex de iciency and o he o ms o p ima y and seconda y lac ic acidosis.49 Mo eo e , PB has also been used as chemical chape one in he ame o o he diseases, eg, in pa ien s wi h a e bilia y diseases associa ed wi h de ec s in he BSEP/ABCB11 anspo e . Au ho con ibu ions LPQ, DRS, and LAE concep ualized and designed he e iew and d a ed he ini ial manusc ip . ML d a ed he manusc ip . All au ho s con ibu ed owa d da a analysis, d a ing and c i ically e ising he pape , and ag ee o be accoun able o all aspec s o he wo k. Disclosu e The au ho s epo no con lic s o in e es in his wo k. Pa ien P e e ence and Adhe ence downloaded om h ps://www.do ep ess.com/ by 193.145.136.228 on 20-Oc -2017 Fo pe sonal use only. Powe ed by TCPDF (www. cpd .o g) 1 / 1 Pa ien P e e ence and Adhe ence 2017:11 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess 1495 Sodium phenylbu y a e g anules o u ea-cycle diso de s Re e ences 1. Suma ML, Dasouki MJ, Scho ield PJ, e al. Physical and linkage map- ping o human ca bamyl phospha e syn he ase I (CPS1) and eassign- men om 2p o 2q35. Cy ogene Cell Gene . 1995;71(3):266–267. 2. Choi JH, Lee BH, Kim JH, e al. Clinical ou comes and he mu a ion spec um o he OTC gene in pa ien s wi h o ni hine ansca bamylase de iciency. J Hum Gene . 2015;60(9):501–507. 3. Engel K, Höhne W, Häbe le J. Mu a ions and polymo phisms in he human a gininosuccina e syn he ase (ASS1) gene. Hum Mu a . 2009; 30(3):300–307. 4. E ez A, Nagamani SC, Lee B. A gininosuccina e lyase de iciency: a gininosuccinic acidu ia and beyond. Am J Med Gene C Semin Med Gene . 2011;157:45–53. 5. Sin YY, Ba on G, Schulze A, Funk CD. A ginase-1 de iciency. J Mol Med (Be l). 2015;93(12):1287–1296. 6. B usilow SW, Ho wich AL. U ea cycle enzymes. In: D i e CR, Beaded AL, Sly WS, Valle D, edi o s. The Me abolic and Molecula Bases o Inhe i ed Disease. New Yo k: McG aw-Hill; 2001:1909–1963. 7. Häbe le J, Boddae N, Bu lina A, e al. Sugges ed guidelines o he diagnosis and managemen o u ea cycle diso de s. O phane J Ra e Dis. 2012;7:32. 8. Suma ML, Koelke S, F eedenbe g D, e al. The incidence o u ea cycle diso de s. Mol Gene Me ab. 2013;110(1–2):179–180. 9. Msall M, Ba shaw ML, Suss R, B usilow SW, Melli s ED. Neu ologic ou come in child en wi h inbo n e o s o u ea syn hesis: ou come o u ea-cycle enzymopa hies. N Engl J Med. 1984;310(23):1500–1505. 10. Bachmann C. Ou come and su i al o 88 pa ien s wi h u ea cycle diso - de s: a e ospec i e e alua ion. Eu J Pedia . 2003;162(6):410–416. 11. Nassogne MC, Hé on B, Toua i G, Rabie D, Saudub ay JM. U ea cycle de ec s: managemen and ou come. J Inhe i Me ab Dis. 2005;28(3): 407–414. 12. Ma ín-He nández E, Aldámiz-Eche a ía L, Cas ejón-Ponce E, e al. U ea cycle diso de s in Spain: an obse a ional, c oss-sec ional and mul icen ic s udy o 104 cases. O phane J Ra e Dis. 2014;9:187. 13. Kölke S, Cazo la AG, Valayannopoulos V, e al. The pheno ypic spec um o o ganic acidu ias and u ea cycle diso de s – pa 1: he ini ial p esen a ion. J Inhe i Me ab Dis. 2015;38(6):1041–1057. 14. Kölke S, Valayannopoulos V, Bu lina AB, e al. The pheno ypic spec- um o o ganic acidu ias and u ea cycle diso de s – pa 2: he e ol ing clinical pheno ype. J Inhe i Me ab Dis. 2015;38(6):1059–1074. 15. K i i zky L, Babikian T, Lee HS, Thomas NH, Bu k-Paull KL, Ba shaw ML. In ellec ual, adap i e, and beha io al unc ioning in child en wi h u ea cycle diso de s. Pedia Res. 2009;66(1):96–101. 16. Holecek M. E idence o a icious cycle in glu amine syn hesis and b eakdown in pa hogenesis o hepa ic encephalopa hy: he apeu ic pe spec i es. Me ab B ain Dis. 2014;29(1):9–17. 17. Be y GT, S eine RD. Long- e m managemen o pa ien s wi h u ea cycle diso de s. J Pedia . 2001;138(1 Suppl):S56–S61. 18. B usilow SW, Maes i NE. U ea cycle diso de s: diagnosis, pa hophysi- ology, and he apy. Ad Pedia . 1996;43:127–170. 19. U ea Cycle Diso de s Con e ence G oup. Consensus s a emen om a con e ence o he managemen o pa ien s wi h u ea cycle diso de s. J Pedia . 2001;138(1 Suppl):S1–S5. 20. Ca baglu [p esc ibing in o ma ion]. Lebanon (NJ): Reco da i Ra e Diseases; 2015. 21. Picca S, Dionisi-Vici C, Abeni D, e al. Ex aco po eal dialysis in neo- na al hype ammonemia: modali ies and p ognos ic indica o s. Pedia Neph ol. 2001;16(11):862–867. 22. Bachmann C. Ou come and su i al o 88 pa ien s wi h u ea cycle diso - de s: a e ospec i e e alua ion. Eu J Pedia . 2003;162(6):410–416. 23. Lewis HB. S udies in he syn hesis o hippu ic acid in he animal o ganisms – II: he syn hesis and a e o elimina ion o hippu ic acid a e benzoa e inges ion in man. J Biol Chem. 1914;18(2):225–231. 24. Ba shaw ML, B usilow S, Wabe L, e al. T ea men o inbo n e o s o u ea syn hesis: ac i a ion o al e na i e pa hways o was e ni ogen syn hesis and exc e ion. N Engl J Med. 1982;306(23):1387–1392. 25. B usilow S, Tinke J, Ba shaw ML. Amino acid acyla ion: a mecha- nism o ni ogen exc e ion in inbo n e o s o u ea syn hesis. Science. 1980;207(4431):659–661. 26. US Food and D ug Adminis a ion. D ug app o al package: Ammonul (sodium phenylace a e and sodium benzoa e) injec ion. 2007. A ailable om: h ps://www.accessda a. da.go /d ugsa da_docs/ nda/2005/020645s000TOC.c m. Accessed Augus 5, 2017. 27. B usilow SW. Phenylace ylglu amine may eplace u ea as a ehicle o was e ni ogen exc e ion. Pedia Res. 1991;29(2):147–150. 28. Ba shaw ML, MacA hu RB, Tuchman M. Al e na i e pa hway he apy o u ea cycle diso de s: wen y yea s la e . J Pedia . 2001; 138(1 Suppl):S46–S55. 29. Eu opean Medicines Agency. Summa y o p oduc cha ac e is ics: Phebu ane. A ailable om: h p://www.ema.eu opa.eu/docs/en_GB/ documen _lib a y/EPAR_-_P oduc _In o ma ion/human/002500/ WC500147373.pd . Accessed Augus 5, 2017. 30. Lee B, Rhead W, Diaz GA, e al. Phase 2 compa ison o a no el ammonia sca enging agen wi h sodium phenylbu y a e in pa ien s wi h u ea cycle diso de s: sa e y, pha macokine ics and ammonia con ol. Mol Gene Me ab. 2010;100(3):221–228. 31. Diaz GA, K i i zky LS, Mokh a ani M, e al. Ammonia con ol and neu ocogni i e ou come among u ea cycle diso de pa ien s ea ed wi h glyce ol phenylbu y a e. Hepa ology. 2013;57(6):2171–2179. 32. Shneide BL, Vockley J. Possible phenylace a e hepa o oxici y du ing 4-phenylbu y a e he apy o Byle disease. J Pedia Gas oen e ol Nu . 2016;62(3):424–428. 33. Ianni i T, Palmie i B. Clinical and expe imen al applica ions o sodium phenylbu y a e. D ugs R D. 2011;11(3):227–249. 34. Holecek M, Vodenica o o a M. Phenylbu y a e exe s ad e se e ec s on li e egene a ion and amino acid concen a ions in pa ially hepa- ec omized a s. In J Exp Pa hol. 2016;97(3):278–284. 35. Rodney S, Boneh A. Amino acid p o iles in pa ien s wi h u ea cycle diso de s a admission o hospi al due o me abolic decompensa ion. JIMD Rep. 2013;9:97–104. 36. Holecek M, Kanda R, Sispe a L, Ko a ik M. Acu e hype ammonemia ac i a es b anched-chain amino acid ca abolism and dec eases hei ex acellula concen a ions: di e en sensi i i y o ed and whi e muscle. Amino Acids. 2011;40(2):575–584. 37. Holecek M, Sp ongl L, Tichý M. E ec o hype ammonemia on leucine and p o ein me abolism in a s. Me abolism. 2000;49(10):1330–1334. 38. Bu age LC, Jain M, Gandol o L, Lee BH. Sodium phenylbu y a e dec eases plasma b anched-chain amino acids in pa ien s wi h u ea cycle diso de s. Mol Gene Me ab. 2014;113(1–2):131–135. 39. Ammonaps 940 mg/g g anules [summa y o p oduc cha ac e is ics]. S ockholm: Swedish O phan Bio i um AB; 2010. 40. B usilow SW, Maes i NE. U ea cycle diso de s: diagnosis, pa hophysi- ology, and he apy. Ad Pedia . 1996;43:127–170. 41. Gu on N, Kibleu Y, Copalu W, Tissen C, B ei k eu z J. De eloping a new o mula ion o sodium phenylbu y a e. A ch Dis Child. 2012; 97(12):1081–1085. 42. Riede M. How swee i isn’ : a new o mula ion o sodium phenylbu- y a e and he challenge o pala abili y o medicines o child en. A ch Dis Child. 2012;97(12):1080. 43. Kibleu Y, Dobbelae e D, Ba h M, B assie A, Gu on N. Resul s om a na ionwide coho empo a y u iliza ion au ho iza ion (ATU) su ey o pa ien s in F ance ea ed wi h Phebu ane (sodium phenylbu y a e) as e-masked g anules. Paedia D ugs. 2014;16(5):407–415. 44. Kibleu Y, Gu on N. Long- e m ollow-up on a coho empo a y u i- liza ion au ho iza ion (ATU) su ey o pa ien s ea ed wi h Phebu ane (sodium phenylbu y a e) as e-masked g anules. Paedia D ugs. 2016; 18(2):139–144. 45. Cede baum S, LeMons C, Ba shaw ML. Al e na i e pa hway o di e - sion he apy o u ea cycle diso de s now and in he u u e. Mol Gene Me ab. 2010;100(3):219–220. 46. Uça SK, Ozba an B, Al inok YA, e al. One yea expe ience o Phe- bu ane (sodium phenylbu y a e) ea men in a pa ien wi h a gininosuc- cina e lyase de iciency. JIMD Rep. 2015;19:31–33. Pa ien P e e ence and Adhe ence downloaded om h ps://www.do ep ess.com/ by 193.145.136.228 on 20-Oc -2017 Fo pe sonal use only. Powe ed by TCPDF (www. cpd .o g) 1 / 1 Pa ien P e e ence and Adhe ence Publish you wo k in his jou nal Submi you manusc ip he e: h p://www.do ep ess.com/pa ien -p e e ence-and-adhe ence-jou nal Pa ien P e e ence and Adhe ence is an in e na ional, pee - e iewed, open access jou nal ha ocuses on he g owing impo ance o pa ien p e e ence and adhe ence h oughou he he apeu ic con inuum. Pa ien sa is ac ion, accep abili y, quali y o li e, compliance, pe sis ence and hei ole in de eloping new he apeu ic modali ies and compounds o op imize clinical ou comes o exis ing disease s a es a e majo a eas o in e es o he jou nal. This jou nal has been accep ed o indexing on PubMed Cen al. The manusc ip managemen sys em is comple ely online and includes a e y quick and ai pee - e iew sys em, which is all easy o use. Visi h p://www. do ep ess.com/ es imonials.php o ead eal quo es om published au ho s. Pa ien P e e ence and Adhe ence 2017:11 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess Do ep ess 1496 Peña-Quin ana e al 47. US Depa men o Heal h and Human Se ices. Die a y Guidelines o Ame icans 2005. Washing on: US Go e nmen P in ing O ice; 2005. 48. Oishi K, Diaz G. Glyce ol phenylbu y a e o he ch onic managemen o u ea cycle diso de s. Expe Re Endoc inol Me ab. 2014;9(5): 427–434. 49. Fe ie o R, Manco G, Laman ea E, e al. Phenylbu y a e he apy o py u a e dehyd ogenase complex de iciency and lac ic acidosis. Sci T ansl Med. 2013;5(175):175 a31. Pa ien P e e ence and Adhe ence downloaded om h ps://www.do ep ess.com/ by 193.145.136.228 on 20-Oc -2017 Fo pe sonal use only. Powe ed by TCPDF (www. cpd .o g) 1 / 1