hegge-1466-73

Phenylketonuria (PKU) is an autoso-mal recessive disease that affects ap-

proximately 1 in 13,500–19,000 new-borns in the US as a result of a deficien-cy of the hepatic enzyme phenylalaninehydroxylase (PAH).1 The incidence ofPKU varies based on ethnicity, with ahigher prevalence among Native Ameri-can and white individuals.2 The primaryresponsibility of PAH is to aid in thecatabolism of the essential amino acidphenylalanine to tyrosine (Figure 1).3

Because of a deficiency in PAH, individ-uals who suffer from PKU have an over-abundance of phenylalanine, which playsan integral role in the development ofnormal brain function. Consequently,central nervous system (CNS) abnormal-ities can result, including impaired braingrowth, microcephaly, and disturbancesin neurotransmitter synthesis.4 If PKUremains undiagnosed or untreated, theseCNS disturbances can lead to serious ir-reparable manifestations, including intel-lectual impairment, seizures, hyperactiv-ity, and gait abnormalities.4,5

Poor metabolic control of phenylala-nine levels has been associated withmagnetic resonance imaging abnormali-ties in children and adults, as well as sig-nificantly lower scores on measures ofIQ, attention, and reaction time.1 Higherphenylalanine levels are also linked with

Author information provided at the end of thetext.

OBJECTIVE: To summarize the role of pharmacotherapy in the management ofphenylketonuria (PKU) and to review the pharmacology, pharmacokinetics,pharmacodynamics, efficacy data, and safety profile of sapropterin for this indi-cation.

DATA SOURCES: A literature search was conducted using MEDLINE (1966–May2009), International Pharmaceutical Abstracts (1970–May 2009), and Cochranedatabase (2008) for the following key words: sapropterin, tetrahydrobiopterin,phenylketonurias, and phenylalanine.

STUDY SELECTION AND DATA EXTRACTION: English-language studies involvinghumans examining the role of tetrahydrobiopterin (BH4) in the management ofPKU were reviewed to evaluate the pharmacology, pharmacokinetics, pharma-codynamics, efficacy data, and safety profile for sapropterin. All Phase 2 and 3randomized controlled trials assessing the safety and efficacy of sapropterin wereincluded in this literature evaluation.

DATA SYNTHESIS: Sapropterin represents the only Food and Drug Administration–approved medication for BH4-responsive PKU, marking an important advance inthe treatment of this condition. Among individuals with hyperphenylalaninemia andsome residual phenylalanine hydroxylase function, sapropterin can enhance activityof this enzyme to decrease serum phenylalanine concentrations. Sapropterin hasbeen compared with placebo in one Phase 2 and one Phase 3 clinical trial, demon-strating significantly better response rates. Based on available studies, this agentappears to be safe and well tolerated, with adverse event rates similar to those ofplacebo. However, additional studies are warranted to assess the long-termsafety and efficacy of sapropterin therapy.

CONCLUSIONS: Sapropterin offers a promising therapeutic option for selectindividuals with BH4-responsive PKU, although long-term data are limited evalu-ating its safety and efficacy in traditional clinical practice settings. Whenconsidering sapropterin therapy, clinicians must consider factors such as costand patient adherence to drug therapy and/or diet.

KEY WORDS: 5,6,7,8-tetrahydrobiopterin, BH4, 6R-BH4, sapropterin, Kuvan,phenylketonurias, phenylalanine.

Ann Pharmacother 2009;43:1466-73.

Published Online, 4 Aug 2009, theannals.com, DOI 10.1345/aph.1M050

THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT

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1466 n The Annals of Pharmacotherapy n 2009 September, Volume 43 theannals.com

Sapropterin: A New Therapeutic Agent for Phenylketonuria

Karly A Hegge, Kristin K Horning, Gregory J Peitz, and Kassy Hegge

Formulary Forum

at Univ Catolica Andres Bello on July 4, 2014aop.sagepub.comDownloaded from

http://aop.sagepub.com/

increased risk for cognitive dysfunction, behavioral diffi-culties, and visual impairment.1,5-7 Therefore, early initia-tion of treatment is critical to minimize these complica-tions. Historically, the treatment of PKU has been solelynonpharmacologic, with affected individuals instructed tofollow a strict, lifelong phenylalanine-restricted diet. Typi-cally, patients require supplementation with specializedformulas to meet their dietary needs, although many indi-viduals with mild hyperphenylalaninemia (HPA) do not re-quire dietary restriction.8

As many as 500 separate genetic mutations have beenlinked to PKU, with different phenotypes displaying vari-ous degrees of disease, including mild HPA (phenylalanineconcentration 2.5–10 mg/dL), mild PKU (phenylalanineconcentration 10–20 mg/dL), and classic PKU (phenylala-nine concentration >20 mg/dL).9,10 In addition to geneticchanges in PAH, the absence of necessary enzymatic co-factors such as tetrahydrobiopterin (BH4) may contributeto abnormal phenylalanine metabolism in affected individ-uals. BH4 serves as a cofactor to PAH in the liver, therebyassisting in the hydroxylation of phenylalanine to tyro-sine.11

To optimize outcomes for affected individuals, phenyl-alanine levels must be closely monitored throughout thepatient’s lifetime. The National Institutes of Health (NIH)has recommended target phenylalanine concentrationsbased on age (Table 1).1 Current efforts focus on maintain-ing these targets beginning during childhood, although a re-strictive diet has also been correlated with improved cogni-tive function even into adulthood.12,13 Dietary measures in-volve limiting intake of foods high in phenylalanine, whichare typically those either high in protein or those containingthe sweetener aspartame (Table 2).14 Unfortunately, adher-ence to current therapy is often suboptimal, as 75% of pa-tients with PKU become essentially nonadherent.15

In an attempt to improve clinical outcomes and patientadherence, research advancements have focused on thedevelopment of a novel pharmacologic option for PKU.After the beneficial effects of BH4 were initially reportedby Kure et al.16 in 1999, an effort ensued to define thisagent’s appropriate place in therapy. With the Food andDrug Administration’s (FDA’s) December 2007 approvalof the orphan drug sapropterin, a promising new thera-peutic option now exists for select patients with HPA andPKU.

Data Sources and Selection

A literature search was conducted using MEDLINE(1966–May 2009), International Pharmaceutical Ab-stracts (1970–May 2009), and Cochrane database (2008)for the following key words: sapropterin, tetrahydrobiop-terin, phenylketonurias, and phenylalanine. References cit-ed in the articles were reviewed for additional information.Studies among humans that examined the role of BH4 inthe treatment of PKU and were published in English werereviewed to evaluate the pharmacology, pharmacokinetics,pharmacodynamics, efficacy data, and safety profile forsapropterin. All Phase 2 and 3 randomized controlled trialsevaluating the safety and efficacy of sapropterin were in-cluded in this literature evaluation.

Clinical Pharmacology

Sapropterin dihydrochloride (Kuvan, BioMarin Pharma-ceutical Inc., Novato, CA), formerly known as Phenoptin,is the first drug to be approved for the treatment of PKU,marking an important advance in the clinical managementof this rare condition.17 Sapropterin is currently indicatedfor the reduction in blood phenylalanine levels among pa-tients with BH4-responsive PKU.

The Annals of Pharmacotherapy n 2009 September, Volume 43 n 1467theannals.com

Figure 1. The metabolism of phenylalanine.3



The PAH enzyme pathway has been the target of contin-ued research, resulting in promising treatment options for asubgroup of patients affected by HPA and PKU.18,19 Earlyversions of exogenous BH4 were a mixture of biologicallyactive (6R-tetrahydro-L-biopterin, or 6R-BH4) and inac-tive (6S-BH4) components.11,20,21 More recently, saprop-terin (6R-BH4), a second-generation orally active synthet-ic formulation consisting of only the biologically activecomponent, has become available for the treatment ofPKU.

Among patients with mild HPA or PKU who maintainsome residual PAH function, exogenous administration oforal 6R-BH4 has been shown to decrease serum phenyl-alanine concentrations. By serving as a cofactor to PAHand thereby enhancing the catabolism of phenylalanine totyrosine, 6R-BH4 may reduce dependence on a phenylala-nine-restricted diet.22,23 Although the exact mechanism ofsapropterin remains unclear, several theories have beenproposed, typically involving alteration of the tertiarystructure of PAH through upregulation, modification, acti-vation, or stabilization.24 Regardless of the specific phar-macology, it appears that oral 6R-BH4 can enhance con-version of phenylalanine to tyrosine, thus physiologicallyaffecting the defective pathway in PKU.

Pharmacokinetics and Pharmacodynamics

Following oral administration of 6R-BH4 to 4 healthyadults, the drug’s plasma profile exhibited first-order kinet-ics, characterized by rapid absorption (0– 4 h) and distribu-tion phases, as well as a long elimination phase (10–33h).25 The maximum plasma concentration following a sin-gle 10-mg/kg dose ranged from 0.0431 to 0.0492 mg/L af-ter 1– 4 hours, while the maximum concentration for a 20-mg/kg dose was 0.0736 mg/L at 3 hours. The drug’s half-life ranged from 3.3 to 5.1 hours among the 4 subjectsstudied. In 1 subject who received both doses, eliminationkinetics appeared to be slightly faster at higher plasmaconcentrations, as shown by the following half-lives (t1/2):4.2 hours (20-mg/kg dose) versus 5.1 hours (10-mg/kgdose). Furthermore, the area under the curve (0–10 h)(AUC0-10 h) was 1.6-fold greater with 20 mg/kg compared

with 10 mg/kg (0.0508 vs 0.0326 mg•h/dL). When givensublingually at 2 mg/kg, plasma concentrations of 6R-BH4were 58–76% higher than concentrations obtained follow-ing oral administration of the same dose.25 However, sub-lingual formulations of sapropterin are not currently avail-able commercially.

In a separate study examining patients with mild HPA(n = 35), mild PKU (n = 19), and classic PKU (n = 17),similar pharmacokinetics were observed following admin-istration of 6R-BH4 20 mg/kg (time to maximum concen-tration 4 h, AUC0-32 h 0.617 mg•h/g Hb in blood).26 As withhealthy subjects, pharmacokinetic parameters for individu-als with HPA or PKU are characterized by a rapid absorp-tion and distribution phase (mean t1/2 1.1 and 2.5 h, respec-tively), followed by a prolonged elimination phase (meant1/2 46 h). Pharmacologic response following oral adminis-tration of 6R-BH4 appears to be delayed, as demonstratedby a reduction in blood phenylalanine concentrations 8–24hours after each dose.

Overall, results of these studies suggest a large variabili-ty of pharmacokinetic parameters among subjects, possi-bly due to the first-pass effect and/or factors affecting gas-trointestinal absorption. Therefore, investigation of thevariability in 6R-BH4 responsiveness among individualswith HPA and PKU is warranted. Although sapropterin ismarketed for once-daily administration, more studies areneeded to examine pharmacokinetic parameters with mul-tiple daily dosing regimens.

Clinical Trials

Although BH4 loading doses originally served as a practi-cal tool for diagnosing BH4 deficiency, the potential thera-peutic role of this agent eventually became apparent. Afterinvestigators initially observed decreased serum phenyl-alanine concentrations following oral BH4 administration,other preliminary studies have supported the safety and ef-ficacy of BH4 supplementation in patients with PAH defi-ciency or PKU.20,22,27-37

To further evaluate the potential therapeutic role of 6R-BH4, one Phase 2 and one Phase 3 trial have assessed thesafety and efficacy of this agent (Table 3). In a Phase 2study, Burton et al.38 evaluated the response to and safetyof short-course 6R-BH4 therapy in subjects with PKU


KA Hegge et al.

Table 1. National Institutes of Health Target Phenylalanine Concentrations1,a

Goal Phenylalanine Subjects Level (mg/dL)

≤12 y of age or pregnant 2–6

>12 y of age if not pregnant 2–10

aRecommended monitoring schedule: weekly intervals during first year,twice monthly from 1 to 12 years of age, and monthly after 12 years ofage.

Table 2. Foods with High Phenylalanine Content14

Aspartame Nuts and seeds

Beef Pork

Cheese Poultry

Eggs Soy products

Fish



who had baseline phenylalanine levels 7.5 mg/dL or more.Following the treatment period, a follow-up blood phenyl-alanine level was determined on day 8. Based on study re-sults, 20% of subjects were classified as responders to 6R-BH4 therapy, defined as a 30% or greater improvement inblood phenylalanine levels compared with baseline. Al-though patients with lower baseline phenylalanine levels(<10 mg/dL) generally demonstrated a greater response, thisfinding was not consistent within each subgroup. 6R-BH4was well tolerated among study participants. Although theoverall response rate in this screening study was lower thanexpected, suitable candidates were identified for a subsequenttrial to further evaluate the safety and efficacy of 6R-BH4.

A Phase 3, multicenter, randomized, double-blind,placebo-controlled trial examined the effects of 6R-BH4among patients with PKU who were previously consideredresponsive to therapy.24 Subjects had either relaxed orabandoned a strict low-phenylalanine diet. Other eligibilitycriteria included a baseline blood phenylalanine concentra-tion of 10 mg/dL or greater (later amended to ≥7.5 mg/dL).Subjects were randomized to receive either 6R-BH4 10mg/kg (n = 42) or placebo (n = 47) once daily for 6 weeks.Blood phenylalanine concentrations were measured atbaseline, which occurred 1–2 weeks prior to randomiza-tion, and at weeks 0, 1, 2, 4, and 6. Mean ± SD baselineblood phenylalanine concentrations in the sapropterin andplacebo groups were 14.0 ± 5.0 and 14.8 ± 5.4 mg/dL, re-spectively. Upon completion of the study, the primary out-come, change in blood phenylalanine concentration frombaseline, favored 6R-BH4 (decrease of 3.9 ± 4.3 vs increaseof 0.1 ± 4.0; p < 0.0001). Furthermore, patients receiving 6R-BH4 were more likely to demonstrate a response to therapy,defined as a 30% or greater reduction in blood phenylalanineconcentration, compared with baseline. Interestingly, somepatients experienced an increase in blood phenylalanine lev-els, although this occurred less frequently in patients receiv-ing 6R-BH4 (17% vs 45% in the placebo group). Unfortu-nately, this study was limited by its small sample size and rel-atively short duration, and little insight was gained regarding

methods to identify potential candidates for 6R-BH4. Al-though all subjects had been previously identified as respon-ders to 6R-BH4 therapy, only 44% demonstrated a similar re-sponse in this subsequent study, suggesting a potential forlessened response over time.

More recently, Lee et al.39 examined subjects with 6R-BH4–responsive PKU in a multicenter, open-label exten-sion study. Participants were previously enrolled in thePhase 3 trial conducted by Levy et al.24 Investigators useda forced dose-titration phase (5, 20, and 10 mg/kg/day ofstudy drug consecutively for 2 wk each), followed by a 4-week dose-analysis phase (10 mg/kg/day) and a 12-weekfixed-dose phase (5, 10, or 20 mg/kg/day based on plasmaphenylalanine concentrations during the initial phase).39

The mean plasma phenylalanine concentration was re-duced during the dose-titration phase and the reductionwas maintained during the final 12 weeks of the study. Al-though this was an open-label study design and includedonly known responders to 6R-BH4 therapy, it does providesupport of a sustained benefit of this agent in patients with6R-BH4–responsive PKU.

Despite promising results in these clinical trials, thelong-term safety and efficacy of 6R-BH4 are not yet clear.Data are sparse supporting its sustained effects or clinicallyrelevant outcomes such as neurologic sequelae. In addi-tion, limited studies have examined the ability of saprop-terin to reduce dependence on dietary phenylalanine re-striction. Trefz et al.23 described the extended use of BH48–12 mg/kg daily in 8 individuals with mild PKU. Aftertreatment periods ranging from 5 to 62 months, 7 of thesubjects required only BH4 treatment, while 1 patient wasable to incorporate a relaxed low-protein diet in conjunc-tion with BH4 supplementation. A separate study assessedlong-term BH4 therapy among 12 subjects for a durationranging from 3 to 56 months.31 Phenylalanine concentra-tions were reduced following single-dose, 4-dose, and 1-week BH4 regimens, leading the authors to conclude thatselect patients taking BH4 may be able to replace or liber-alize their reduced-phenylalanine diets. Finally, Steinfeld



Table 3. Summary of Clinical Trials

Pts., Pts. Trial Design N Age, y Interventiona Duration Results

Burton OL, 485 ≥8 (mean 21.8; sapropterin 10 mg/kg 8 days response rate: 20%b

(2007)38 screening 78% <12) daily

Levy RCT 89 ≥8 (mean 20) sapropterin 10 mg/kg 6 wk response rate: 44% with 6R-BH4 vs 9% with placebob

(2007)24 daily vs placebo

Lee OL, 80 ≥8 (mean 20.4) sapropterin 5, 10, 22 wk reduction in mean plasma phenylalanine (from 14.7 at(2008)39 extension or 20 mg/kg daily baseline to 10.7 mg/dL at week 10, then maintained

through week 22)

OL = open-label; RCT = randomized controlled trial.aAll patients instructed to continue current diet.bDefinition of response: ≥30% reduction in phenylalanine concentrations compared with baseline.



et al.40 reported successful treatment of 2 infants with mildPKU using BH4 10–20 mg/kg once daily, resulting in ade-quate control of serum phenylalanine concentrations forover 2 years without additional dietary modifications.However, the ability of patients taking BH4 to relax depen-dence on a phenylalanine-restricted diet requires furtherevaluation in large, randomized clinical trials.

Safety

Based on available data from Phase 2 and 3 clinical tri-als, sapropterin appears to be safe and well tolerated.24,38

The most commonly reported adverse events are minor inseverity and include headache (15%), upper respiratorytract infection (12%), rhinorrhea (11%), pharyngolaryngealpain (10%), and gastrointestinal complaints.22 However,the incidence of these adverse events is not significantlydifferent compared with placebo, and no serious allergicreactions have been observed in clinical trials. Long-termeffects of sapropterin, including neurologic sequelae, havenot been evaluated. The potential exists for sapropterin tointerfere with concurrent drug therapy, and possible clini-cally relevant drug interactions are listed in Table 4.17 Lim-ited data exist on examination of sapropterin in special pa-tient populations, particularly in young children, pregnan-cy, or individuals with renal or hepatic impairment.

Dosage and Patient Counseling

The manufacturer’s suggested starting dose is 10 mg/kgonce daily, with appropriate dosage adjustments recom-mended in 1-month intervals.17 If no improvement is ob-served, the dose should be increased to 20 mg/kg once dai-ly. The usual maintenance dose is 5–20 mg/kg once daily.Sapropterin may be discontinued in patients who do not re-spond to dosages within this range.

An alternative dosing method has also been proposed toallow for closer monitoring of phenylalanine levels when

initiating therapy. To determine responsiveness to saprop-terin, an initial trial dose of 20 mg/kg once daily may beused, although a lower dose may be appropriate if adverseeffects occur. Blood phenylalanine levels can be measured atbaseline and on days 1, 7, 14, and 28.41 Since dietary adher-ence may influence sapropterin response, patients should beencouraged to maintain a consistent diet during this trial pe-riod. For patients defined as nonresponders to sapropterintherapy (<30% reduction in blood phenylalanine concentra-tions vs baseline), this drug should be discontinued. Forthose who respond to therapy, sapropterin can be contin-ued at a maintenance dose of 5–20 mg/kg once daily.17

Sapropterin is supplied as a 100-mg tablet, which shouldbe dissolved into 120–240 mL of water or apple juice andadministered orally within 15 minutes of dissolution.17

Many patients may require 2 or more tablets per day, sopill burden may affect adherence to sapropterin therapy.However, multiple tablets can be dissolved in the samevolume of fluid. To enhance absorption and minimize gas-trointestinal intolerance, this agent should be taken with ei-ther food or supplemental formula. For maintenancesapropterin therapy, frequent monitoring of phenylalaninelevels is extremely important to ensure that treatment goalsare being achieved (Table 1).

Since obtaining insurance coverage for sapropterin ther-apy can be challenging, the manufacturer of this drug hasincorporated measures to facilitate the insurance approvalprocess. Regardless of insurance or income status, all pa-tients who are prescribed sapropterin must use the BioMarinPatient and Physician Support Program to obtain the drugfrom a specialty pharmacy.42 However, patients will likelyrely primarily on their pharmacists and physicians for appro-priate education regarding sapropterin therapy.

Special Populations

NEONATES AND YOUNG CHILDREN

Routine screening for PKU is recommended at birth,with appropriate dietary interventions implemented promptlyfor individuals with this rare genetic disorder. Evidencesupports maintaining target blood phenylalanine concen-trations as soon after diagnosis as possible. However, therole of sapropterin in neonates or children under age 8 hasnot yet been established due to a lack of safety and efficacydata.17 With continued interest in treatment options for thisimportant subgroup of patients with PKU, researchers maysoon define the role for sapropterin in young children.

MATERNAL PKU

Although randomized clinical trials involving saprop-terin have excluded pregnant women, this population re-mains a key area of interest. Koch et al.43 described effec-tive blood phenylalanine control with BH4 in the treatment


KA Hegge et al.

Table 4. Potential Drug Interactions with Sapropterin17

Drugs Effect of Interaction

Folic acid antagonists decreased BH4 levels via dihydrop-(methotrexate) teridine reductase enzyme

inhibition

Levodopa seizure, overstimulation, irritabilitya

Phosphodiesterase-5 inhibitors additive effect on nitric oxide–(sildenafil, tadalafil, vardenafil) mediated vasorelaxation,

contributing to increased risk for hypotensionb

BH4 = tetrahydrobiopterin.aReported in non-phenylketonuria trials, but caution is recommendedin all patients.

bTheoretical risk that has not been confirmed due to lack of studiesevaluating levodopa in combination with sapropterin.



of a maternal PKU pregnancy, but the dose was much low-er than the recommended dose for PKU in nonpregnantpatients. Sapropterin is listed as pregnancy category C andhas not been approved for use in maternal PKU pregnancy,although the future role of this agent in pregnant womenwith PKU remains unclear.

Therapeutic Issues and Controversies

Sapropterin, the first medication approved for BH4-re-sponsive PKU, may offer promise for individuals strug-gling to control their phenylalanine concentrations withdiet alone. However, additional studies must examine therole of sapropterin in easing dependence on a strict pheny-lalanine-restricted diet. As suggested by Levy et al.,41 indi-viduals with a good response to sapropterin may choose togradually add phenylalanine-containing products to theirdiet, although frequent monitoring of blood phenylalanineconcentrations is appropriate during this time period. Tol-erance of dietary adjustment may vary among individualsand should be based on a detailed dietary assessment and adocumented response to the addition of milk and/or eggpowder to the diet. Sapropterin is currently indicated forthe treatment of BH4-responsive PKU as an adjunct to areduced phenylalanine diet.

In addition to the unknown effects of sapropterin on di-etary phenylalanine tolerance, other considerations may limitthe routine use of this medication in traditional practice set-tings. Studies examining sapropterin for PKU have assessedsurrogate outcome measures, namely serum phenylalanineconcentrations, although more clinically relevant outcomesmay be more appropriate, such as neurologic sequelae or ef-fects on quality of life. Most studies have defined a responseto sapropterin as a reduction in blood phenylalanine concen-trations of at least 30%. However, since target phenylalanineconcentrations have been recommended by the NIH, theability to achieve these suggested targets may provide moreclinically meaningful insight regarding the true benefits ofsapropterin. Furthermore, data are sparse examiningsapropterin in subjects less than 4 years old or in those whoare pregnant. These patient populations will likely be targetsof future studies due to the potential of sapropterin to provideconsiderable benefit over traditional treatment approaches.The lack of a consistent effect among subgroups with variousbaseline phenylalanine concentrations makes prediction ofsapropterin response challenging. Finally, some subjects inPhase 2 and 3 trials demonstrated a lessened response tosapropterin over time, suggesting that its sustained benefit re-quires further investigation.

Currently, the marketability of sapropterin may besomewhat limited due to the low prevalence of PKU, thelack of consistent response among affected individuals,and the high cost of therapy. Dietary supplementation andthe need for routine monitoring of phenylalanine levels can

be expensive, and sapropterin could cost the average pa-tient an additional $57,000 per year.44 Phase 2 clinical trialsare underway to examine the drug’s potential benefit inother prevalent conditions, including coronary artery dis-ease, hypertension, peripheral arterial disease, and sicklecell disease.45 Based on results of these ongoing studies, aswell as other trials involving patients with mild HPA andPKU, the role of sapropterin may eventually be expandedto a larger portion of the US population.

Summary and Formulary Recommendations

Sapropterin, the first FDA-approved medication forPKU, enhances PAH activity in BH4-responsive subjects,offering a promising therapeutic option for the manage-ment of this condition. Based on populations studied inclinical trials, it seems that the role of sapropterin is bestdefined in patients with baseline phenylalanine levelsgreater than 7.5 mg/dL who demonstrate a response totherapy. Therefore, it appears that many patients over age 8with mild or classic PKU, as well as certain patients withmild HPA, are candidates for a trial course of sapropterintherapy to determine whether they are responders, since aprediction of response is not possible at this time.

Although studies have demonstrated a decrease in serumphenylalanine concentration among select patients withPKU, long-term safety and efficacy data are limited. Fur-thermore, key patient populations have not yet been stud-ied, and the high cost of this agent remains a concern formany patients and providers. Thus, the true benefit of saprop-terin in clinical practice settings remains unclear, and fur-ther studies are necessary in order to more clearly defineits role in the treatment of PKU.

Karly A Hegge PharmD BCPS, Clinical Pharmacist, Falls Com-munity Health; Assistant Professor of Pharmacy Practice, Collegeof Pharmacy, South Dakota State University, Sioux Falls, SD Kristin K Horning PharmD BCPS, Clinical Pharmacist, East DesMoines Family Care Center; Assistant Professor (Clinical), Collegeof Pharmacy, University of Iowa, Des Moines, IA Gregory J Peitz PharmD BCPS, Clinical Pharmacist, Sanford USDMedical Center, Sioux Falls, SDKassy Hegge MD, Pediatric Resident Physician, Mayo Clinic,Rochester, MNReprints: Dr. Karly Hegge, College of Pharmacy, South DakotaState University, University Center North, 4801 N. Career Ave., SiouxFalls, SD 57106, fax 605/367-8423, [email protected]

Financial disclosure: None reported

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25. Fiege B, Ballhausen D, Kierat L, et al. Plasma tetrahydrobiopterin and itspharmacokinetics following oral administration. Mol Genet Metab 2004;81:45-51.

26. Zurflüh MR, Fiori L, Fiege B, et al. Pharmacokinetics of orally adminis-tered tetrahydrobiopterin in patients with phenylalanine hydroxylase de-ficiency. J Inherit Metab Dis 2006;29:725-31.

27. Muntau AC, Roschinger W, Habich M, et al. Tetrahydrobiopterin as analternative treatment for mild phenylketonuria. N Engl J Med 2002;347:2122-32.

28. Spaapen LJ, Rubio-Gonzalbo ME. Tetrahydrobiopterin–phenylalaninehydroxylase deficiency, state of the art. Mol Genet Metab 2003;78:93-9.

29. Hennermann JB, Bührer C, Blau N, Vetter B, Mönch E. Long-term treat-ment with tetrahydrobiopterin increases phenylalanine tolerance in chil-dren with severe phenotype of phenylketonuria. Mol Genet Metab 2005;86(suppl):86S-90S.

30. Lambruschini N, Pérez-Dueñas B, Vilaseca MA, et al. Clinical and nutri-tional evaluation of phenylketonuric patients on tetrahydrobiopterinmonotherapy. Mol Genet Metab 2005;86(suppl):54S-60S.

31. Shintaku H, Kure S, Ohura T, et al. Long-term treatment and diagnosisof tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutantphenylalanine hydroxylase gene. Pediatr Res 2004;55:425-30.

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35. Desviat LR, Perez B, Belanger-Quintana A, et al. Tetrahydrobiopterin re-sponsiveness: results of the BH4 loading test in 31 Spanish PKU patientsand correlation with their genotype. Mol Genet Metab 2004;83:157-62.

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Sapropterina: Un Agente Terapéutico Nuevo Para Fenilcetonuria

KA Hegge, KK Horning, GJ Peitz, y K Hegge


EXTRACTO

OBJETIVO: Resumir el papel de la farmacoterapia en el manejo de fenilceto-nuria (FCU) y revisar la farmacología, farmacocinética, farmacodinámica,datos de eficacia, y perfil de seguridad de sapropterina para esta indicación.


KA Hegge et al.





FUENTES DE INFORMACIÓN: Se llevó a cabo una búsqueda de literaturausando MEDLINE (1966–mayo 2009), Extractos FarmacéuticosInternacionales (1970–mayo 2009), y base de datos Cochrane (2008)para las siguientes palabras claves: sapropterina, tetrahidrobiopterina,fenilcetonurias, y fenilalanina.

SELECCIÓN DE FUENTES DE INFORMACIÓN Y MÉTODO DE EXTRACCIÓN DE

INFORMACIÓN: Se revisaron estudios en humanos publicados en el idiomainglés los cuales examinaron el papel de tetrahidrobiopterina (BH4) enel manejo de FCU para evaluar la farmacología, farmacocinética, farma-codinámica, datos de eficacia, y perfil de seguridad de sapropterina.Todos los estudios controlados aleatorios fase 2 y 3 que evaluaron laseguridad y eficacia de sapropterina fueron incluidos en esta evaluaciónde la literatura.

SÍNTESIS: La sapropterina representa el único fármaco aprobado por laAdministración de Drogas y Alimentos para FCU que responde a BH4,lo que marca un avance importante en el tratamiento de esta condición.La sapropterina puede aumentar la actividad de la enzima hidroxilasa defenilalanina para disminuir las concentraciones séricas de fenilalanina enlos pacientes con hiperfenilalaninemia y alguna función residual de estaenzima. La sapropterina ha sido comparada a placebo en un estudio fase2 y otro fase 3 demostrando una respuesta significativamente mejor.Este agente parece ser seguro y bien tolerado con una incidencia deeventos adversos similar a placebo basado en los estudios disponibles.Sin embargo, se necesitan estudios adicionales para evaluar la seguridady eficacia a largo plazo de la terapia de sapropterina.

CONCLUSIONES: La sapropterina ofrece una opción terapéutica prometedorapara individuos selectos con FCU que responde a BH4, aunque los datosa largo plazo evaluando su seguridad y eficacia en escenarios de prácticaclínica tradicionales son limitados. Se recomienda que los clínicos debentomar en cuenta factores como costo y la adherencia del paciente almedicamento y/o dieta cuando se considere la terapia de sapropterina.

Traducido por Juan F Feliú

Saproptérine: un Nouvel Agent Thérapeutique pour le Traitement dela Phénylcétonurie

KA Hegge, KK Horning, GJ Peitz, et K Hegge


RÉSUMÉ

OBJECTIF: Résumer le rôle de la pharmacothérapie dans la prise en chargede la phénylcétonurie et revoir la pharmacologie, la pharmacocinétique,la pharmacodynamie, les données d’efficacité, et le profil d’innocuité dela saproptérine pour cette indication.

REVUE DE LA LITTÉRATURE: Une recherche de la littérature a été faite dansles banques de données informatisée MEDLINE (1966–mai 2009),International Pharmaceutique Résumé (1970–mai 2009), et Cochrane(2008) à l’aide des mots-clé suivants: saproptérine, tétrahydrobioptérine,phénylcétonurie, et phénylalanine.

SÉLECTION DES ÉTUDES ET DE L’INFORMATION: Les études chez l’humainpubliées en langue anglaise et concernant le rôle de la tétrabioptérine(BH4) pour le traitement de la phénylcétonurie ont été revues afind’évaluer la pharmacologie, la pharmacocinétique, la pharmacodynamie,les données d’efficacité, et le profil d’innocuité de la saproptérine.Toutes les études de phase 2 et 3, randomisées et contrôlées, évaluantl’innocuité et l’efficacité de la saproptérine ont été incluses dans cetteévaluation de la littérature.

RÉSUMÉ: La saproptérine représente le seul médicament approuvé par laFDA pour le traitement de la phénylcétonurie répondant au BH4, marquantainsi une importante avancée dans le traitement de cette condition. Chezles individus présentant une hyperphénylalaninémie et une activitérésiduelle de la phénylalanine hydroxylase, la saproptérine peut augmenterl’activité de cette enzyme et permettre de diminuer davantage les concen-trations sériques de phénylalanine. La saproptérine a été comparée à unplacebo dans un essai clinique de phase 2 et un autre de phase 3, celle-cidémontrant de meilleurs taux de réponse. En se basant sur les donnéesdes études disponibles, cet agent semble sécuritaire et bien toléré,présentant un taux d’effets indésirables semblable à celui du placebo.Cependant, d’autres études sont nécessaires afin d’évaluer l’innocuité etl’efficacité à long terme de la saproptérine.

CONCLUSIONS: La saproptérine offre une option thérapeutique prometteusepour certains individus présentant une phénylcétonurie qui répond auBH4, même si des données à long terme évaluant son innocuité et sonefficacité dans un cadre de pratique clinique sont manquantes. Lorsquele clinicien envisage un traitement par la saproptérine, d’autres facteurscomme le coût du traitement et l’adhésion du patient au traitement et à ladiète doivent aussi être pris en compte.

Traduit par Denyse Demers



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