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Phenylketonuria is an autosomal recessive disease that affects 1 in 13,500-19,000 newborns in the US. The primary responsibility of PAH is to aid in the catabolism of the essential amino acid phenylalanine to tyrosine. Sapropterin has been used to treat PKU for more than 20 years.
Phenylketonuria is an autosomal recessive disease that affects 1 in 13,500-19,000 newborns in the US. The primary responsibility of PAH is to aid in the catabolism of the essential amino acid phenylalanine to tyrosine. Sapropterin has been used to treat PKU for more than 20 years.
Phenylketonuria is an autosomal recessive disease that affects 1 in 13,500-19,000 newborns in the US. The primary responsibility of PAH is to aid in the catabolism of the essential amino acid phenylalanine to tyrosine. Sapropterin has been used to treat PKU for more than 20 years.
mal recessive disease that affects ap- proximately 1 in 13,50019,000 new- borns in the US as a result of a deficien- cy of the hepatic enzyme phenylalanine hydroxylase (PAH). 1 The incidence of PKU varies based on ethnicity, with a higher prevalence among Native Ameri- can and white individuals. 2 The primary responsibility of PAH is to aid in the catabolism of the essential amino acid phenylalanine to tyrosine (Figure 1). 3 Because of a deficiency in PAH, individ- uals who suffer from PKU have an over- abundance of phenylalanine, which plays an integral role in the development of normal brain function. Consequently, central nervous system (CNS) abnormal- ities can result, including impaired brain growth, microcephaly, and disturbances in neurotransmitter synthesis. 4 If PKU remains undiagnosed or untreated, these CNS 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 with magnetic resonance imaging abnormali- ties in children and adults, as well as sig- nificantly lower scores on measures of IQ, attention, and reaction time. 1 Higher phenylalanine levels are also linked with Author information provided at the end of the text. OBJECTIVE: To summarize the role of pharmacotherapy in the management of phenylketonuria (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 (1966May 2009), International Pharmaceutical Abstracts (1970May 2009), and Cochrane database (2008) for the following key words: sapropterin, tetrahydrobiopterin, phenylketonurias, and phenylalanine. STUDY SELECTION AND DATA EXTRACTION: English-language studies involving humans examining the role of tetrahydrobiopterin (BH4) in the management of PKU were reviewed to evaluate the pharmacology, pharmacokinetics, pharma- codynamics, efficacy data, and safety profile for sapropterin. All Phase 2 and 3 randomized controlled trials assessing the safety and efficacy of sapropterin were included in this literature evaluation. DATA SYNTHESIS: Sapropterin represents the only Food and Drug Administration approved medication for BH4-responsive PKU, marking an important advance in the treatment of this condition. Among individuals with hyperphenylalaninemia and some residual phenylalanine hydroxylase function, sapropterin can enhance activity of this enzyme to decrease serum phenylalanine concentrations. Sapropterin has been compared with placebo in one Phase 2 and one Phase 3 clinical trial, demon- strating significantly better response rates. Based on available studies, this agent appears to be safe and well tolerated, with adverse event rates similar to those of placebo. However, additional studies are warranted to assess the long-term safety and efficacy of sapropterin therapy. CONCLUSIONS: Sapropterin offers a promising therapeutic option for select individuals with BH4-responsive PKU, although long-term data are limited evalu- ating its safety and efficacy in traditional clinical practice settings. When considering sapropterin therapy, clinicians must consider factors such as cost and 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 ACPE UNIVERSAL PROGRAM NUMBER: 407-000-09-015-H01-P A For Our Patients summary of this article is available at ForOurPatients.info 1466 I The Annals of Pharmacotherapy I 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, 2014 aop.sagepub.com Downloaded from 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 solely nonpharmacologic, with affected individuals instructed to follow a strict, lifelong phenylalanine-restricted diet. Typi- cally, patients require supplementation with specialized formulas 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 been linked to PKU, with different phenotypes displaying vari- ous degrees of disease, including mild HPA (phenylalanine concentration 2.510 mg/dL), mild PKU (phenylalanine concentration 1020 mg/dL), and classic PKU (phenylala- nine concentration >20 mg/dL). 9,10 In addition to genetic changes in PAH, the absence of necessary enzymatic co- factors such as tetrahydrobiopterin (BH4) may contribute to abnormal phenylalanine metabolism in affected individ- uals. BH4 serves as a cofactor to PAH in the liver, thereby assisting in the hydroxylation of phenylalanine to tyro- sine. 11 To optimize outcomes for affected individuals, phenyl- alanine levels must be closely monitored throughout the patients lifetime. The National Institutes of Health (NIH) has recommended target phenylalanine concentrations based 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, which are typically those either high in protein or those containing the 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 patient adherence, research advancements have focused on the development of a novel pharmacologic option for PKU. After the beneficial effects of BH4 were initially reported by Kure et al. 16 in 1999, an effort ensued to define this agents appropriate place in therapy. With the Food and Drug Administrations (FDAs) December 2007 approval of the orphan drug sapropterin, a promising new thera- peutic option now exists for select patients with HPA and PKU. Data Sources and Selection A literature search was conducted using MEDLINE (1966May 2009), International Pharmaceutical Ab- stracts (1970May 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 in the treatment of PKU and were published in English were reviewed to evaluate the pharmacology, pharmacokinetics, pharmacodynamics, efficacy data, and safety profile for sapropterin. All Phase 2 and 3 randomized controlled trials evaluating 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 management of this rare condition. 17 Sapropterin is currently indicated for the reduction in blood phenylalanine levels among pa- tients with BH4-responsive PKU. The Annals of Pharmacotherapy I 2009 September, Volume 43 I 1467 theannals.com Figure 1. The metabolism of phenylalanine. 3 at Univ Catolica Andres Bello on July 4, 2014 aop.sagepub.com Downloaded from The PAH enzyme pathway has been the target of contin- ued research, resulting in promising treatment options for a subgroup of patients affected by HPA and PKU. 18,19 Early versions of exogenous BH4 were a mixture of biologically active (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 active component, has become available for the treatment of PKU. Among patients with mild HPA or PKU who maintain some residual PAH function, exogenous administration of oral 6R-BH4 has been shown to decrease serum phenyl- alanine concentrations. By serving as a cofactor to PAH and thereby enhancing the catabolism of phenylalanine to tyrosine, 6R-BH4 may reduce dependence on a phenylala- nine-restricted diet. 22,23 Although the exact mechanism of sapropterin remains unclear, several theories have been proposed, typically involving alteration of the tertiary structure 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 physiologically affecting the defective pathway in PKU. Pharmacokinetics and Pharmacodynamics Following oral administration of 6R-BH4 to 4 healthy adults, the drugs plasma profile exhibited first-order kinet- ics, characterized by rapid absorption (04 h) and distribu- tion phases, as well as a long elimination phase (1033 h). 25 The maximum plasma concentration following a sin- gle 10-mg/kg dose ranged from 0.0431 to 0.0492 mg/L af- ter 14 hours, while the maximum concentration for a 20- mg/kg dose was 0.0736 mg/L at 3 hours. The drugs half- life ranged from 3.3 to 5.1 hours among the 4 subjects studied. In 1 subject who received both doses, elimination kinetics appeared to be slightly faster at higher plasma concentrations, as shown by the following half-lives (t 1/2 ): 4.2 hours (20-mg/kg dose) versus 5.1 hours (10-mg/kg dose). Furthermore, the area under the curve (010 h) (AUC 0-10 h ) was 1.6-fold greater with 20 mg/kg compared with 10 mg/kg (0.0508 vs 0.0326 mgh/dL). When given sublingually at 2 mg/kg, plasma concentrations of 6R-BH4 were 5876% 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, AUC 0-32 h 0.617 mgh/g Hb in blood). 26 As with healthy subjects, pharmacokinetic parameters for individu- als with HPA or PKU are characterized by a rapid absorp- tion and distribution phase (mean t 1/2 1.1 and 2.5 h, respec- tively), followed by a prolonged elimination phase (mean t 1/2 46 h). Pharmacologic response following oral adminis- tration of 6R-BH4 appears to be delayed, as demonstrated by a reduction in blood phenylalanine concentrations 824 hours 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 the variability in 6R-BH4 responsiveness among individuals with HPA and PKU is warranted. Although sapropterin is marketed for once-daily administration, more studies are needed 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. After investigators 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 the safety and efficacy of this agent (Table 3). In a Phase 2 study, Burton et al. 38 evaluated the response to and safety of short-course 6R-BH4 therapy in subjects with PKU 1468 I The Annals of Pharmacotherapy I 2009 September, Volume 43 theannals.com KA Hegge et al. Table 1. National Institutes of Health Target Phenylalanine Concentrations 1,a Goal Phenylalanine Subjects Level (mg/dL) 12 y of age or pregnant 26 >12 y of age if not pregnant 210 a Recommended monitoring schedule: weekly intervals during first year, twice monthly from 1 to 12 years of age, and monthly after 12 years of age. Table 2. Foods with High Phenylalanine Content 14 Aspartame Nuts and seeds Beef Pork Cheese Poultry Eggs Soy products Fish at Univ Catolica Andres Bello on July 4, 2014 aop.sagepub.com Downloaded from 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 in blood phenylalanine levels compared with baseline. Al- though patients with lower baseline phenylalanine levels (<10 mg/dL) generally demonstrated a greater response, this finding was not consistent within each subgroup. 6R-BH4 was well tolerated among study participants. Although the overall response rate in this screening study was lower than expected, suitable candidates were identified for a subsequent trial 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-BH4 among patients with PKU who were previously considered responsive to therapy. 24 Subjects had either relaxed or abandoned a strict low-phenylalanine diet. Other eligibility criteria 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 10 mg/kg (n = 42) or placebo (n = 47) once daily for 6 weeks. Blood phenylalanine concentrations were measured at baseline, which occurred 12 weeks prior to randomiza- tion, and at weeks 0, 1, 2, 4, and 6. Mean SD baseline blood phenylalanine concentrations in the sapropterin and placebo 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 from baseline, favored 6R-BH4 (decrease of 3.9 4.3 vs increase of 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 phenylalanine concentration, compared with baseline. Interestingly, some patients 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 for lessened response over time. More recently, Lee et al. 39 examined subjects with 6R- BH4responsive PKU in a multicenter, open-label exten- sion study. Participants were previously enrolled in the Phase 3 trial conducted by Levy et al. 24 Investigators used a forced dose-titration phase (5, 20, and 10 mg/kg/day of study drug consecutively for 2 wk each), followed by a 4- week dose-analysis phase (10 mg/kg/day) and a 12-week fixed-dose phase (5, 10, or 20 mg/kg/day based on plasma phenylalanine concentrations during the initial phase). 39 The mean plasma phenylalanine concentration was re- duced during the dose-titration phase and the reduction was maintained during the final 12 weeks of the study. Al- though this was an open-label study design and included only known responders to 6R-BH4 therapy, it does provide support of a sustained benefit of this agent in patients with 6R-BH4responsive PKU. Despite promising results in these clinical trials, the long-termsafety and efficacy of 6R-BH4 are not yet clear. Data are sparse supporting its sustained effects or clinically relevant 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 BH4 812 mg/kg daily in 8 individuals with mild PKU. After treatment periods ranging from 5 to 62 months, 7 of the subjects required only BH4 treatment, while 1 patient was able to incorporate a relaxed low-protein diet in conjunc- tion with BH4 supplementation. A separate study assessed long-term BH4 therapy among 12 subjects for a duration ranging 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 that select patients taking BH4 may be able to replace or liber- alize their reduced-phenylalanine diets. Finally, Steinfeld Sapropterin: A New Therapeutic Agent for Phenylketonuria The Annals of Pharmacotherapy I 2009 September, Volume 43 I 1469 theannals.com Table 3. Summary of Clinical Trials Pts., Pts. Trial Design N Age, y Intervention a 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 placebo b (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. a All patients instructed to continue current diet. b Definition of response: 30% reduction in phenylalanine concentrations compared with baseline. at Univ Catolica Andres Bello on July 4, 2014 aop.sagepub.com Downloaded from et al. 40 reported successful treatment of 2 infants with mild PKU using BH4 1020 mg/kg once daily, resulting in ade- quate control of serum phenylalanine concentrations for over 2 years without additional dietary modifications. However, the ability of patients taking BH4 to relax depen- dence on a phenylalanine-restricted diet requires further evaluation 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 in severity and include headache (15%), upper respiratory tract infection (12%), rhinorrhea (11%), pharyngolaryngeal pain (10%), and gastrointestinal complaints. 22 However, the incidence of these adverse events is not significantly different compared with placebo, and no serious allergic reactions have been observed in clinical trials. Long-term effects of sapropterin, including neurologic sequelae, have not been evaluated. The potential exists for sapropterin to interfere 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 manufacturers suggested starting dose is 10 mg/kg once 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 520 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 to allow 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 be used, although a lower dose may be appropriate if adverse effects occur. Blood phenylalanine levels can be measured at baseline and on days 1, 7, 14, and 28. 41 Since dietary adher- ence may influence sapropterin response, patients should be encouraged to maintain a consistent diet during this trial pe- riod. For patients defined as nonresponders to sapropterin therapy (<30% reduction in blood phenylalanine concentra- tions vs baseline), this drug should be discontinued. For those who respond to therapy, sapropterin can be contin- ued at a maintenance dose of 520 mg/kg once daily. 17 Sapropterin is supplied as a 100-mg tablet, which should be dissolved into 120240 mL of water or apple juice and administered orally within 15 minutes of dissolution. 17 Many patients may require 2 or more tablets per day, so pill burden may affect adherence to sapropterin therapy. However, multiple tablets can be dissolved in the same volume of fluid. To enhance absorption and minimize gas- trointestinal intolerance, this agent should be taken with ei- ther food or supplemental formula. For maintenance sapropterin therapy, frequent monitoring of phenylalanine levels is extremely important to ensure that treatment goals are being achieved (Table 1). Since obtaining insurance coverage for sapropterin ther- apy can be challenging, the manufacturer of this drug has incorporated measures to facilitate the insurance approval process. Regardless of insurance or income status, all pa- tients who are prescribed sapropterin must use the BioMarin Patient and Physician Support Program to obtain the drug from a specialty pharmacy. 42 However, patients will likely rely 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 promptly for individuals with this rare genetic disorder. Evidence supports maintaining target blood phenylalanine concen- trations as soon after diagnosis as possible. However, the role of sapropterin in neonates or children under age 8 has not yet been established due to a lack of safety and efficacy data. 17 With continued interest in treatment options for this important subgroup of patients with PKU, researchers may soon 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 1470 I The Annals of Pharmacotherapy I 2009 September, Volume 43 theannals.com KA Hegge et al. Table 4. Potential Drug Interactions with Sapropterin 17 Drugs Effect of Interaction Folic acid antagonists decreased BH4 levels via dihydrop- (methotrexate) teridine reductase enzyme inhibition Levodopa seizure, overstimulation, irritability a Phosphodiesterase-5 inhibitors additive effect on nitric oxide (sildenafil, tadalafil, vardenafil) mediated vasorelaxation, contributing to increased risk for hypotension b BH4 = tetrahydrobiopterin. a Reported in non-phenylketonuria trials, but caution is recommended in all patients. b Theoretical risk that has not been confirmed due to lack of studies evaluating levodopa in combination with sapropterin. at Univ Catolica Andres Bello on July 4, 2014 aop.sagepub.com Downloaded from of a maternal PKU pregnancy, but the dose was much low- er than the recommended dose for PKU in nonpregnant patients. Sapropterin is listed as pregnancy category C and has not been approved for use in maternal PKU pregnancy, although the future role of this agent in pregnant women with 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 with diet alone. However, additional studies must examine the role 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 to gradually add phenylalanine-containing products to their diet, although frequent monitoring of blood phenylalanine concentrations is appropriate during this time period. Tol- erance of dietary adjustment may vary among individuals and should be based on a detailed dietary assessment and a documented response to the addition of milk and/or egg powder to the diet. Sapropterin is currently indicated for the treatment of BH4-responsive PKU as an adjunct to a reduced phenylalanine diet. In addition to the unknown effects of sapropterin on di- etary phenylalanine tolerance, other considerations may limit the routine use of this medication in traditional practice set- tings. Studies examining sapropterin for PKU have assessed surrogate outcome measures, namely serum phenylalanine concentrations, although more clinically relevant outcomes may be more appropriate, such as neurologic sequelae or ef- fects on quality of life. Most studies have defined a response to sapropterin as a reduction in blood phenylalanine concen- trations of at least 30%. However, since target phenylalanine concentrations have been recommended by the NIH, the ability to achieve these suggested targets may provide more clinically meaningful insight regarding the true benefits of sapropterin. Furthermore, data are sparse examining sapropterin in subjects less than 4 years old or in those who are pregnant. These patient populations will likely be targets of future studies due to the potential of sapropterin to provide considerable benefit over traditional treatment approaches. The lack of a consistent effect among subgroups with various baseline phenylalanine concentrations makes prediction of sapropterin response challenging. Finally, some subjects in Phase 2 and 3 trials demonstrated a lessened response to sapropterin over time, suggesting that its sustained benefit re- quires further investigation. Currently, the marketability of sapropterin may be somewhat limited due to the low prevalence of PKU, the lack of consistent response among affected individuals, and the high cost of therapy. Dietary supplementation and the 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 trials are underway to examine the drugs potential benefit in other prevalent conditions, including coronary artery dis- ease, hypertension, peripheral arterial disease, and sickle cell disease. 45 Based on results of these ongoing studies, as well as other trials involving patients with mild HPA and PKU, the role of sapropterin may eventually be expanded to a larger portion of the US population. Summary and Formulary Recommendations Sapropterin, the first FDA-approved medication for PKU, enhances PAH activity in BH4-responsive subjects, offering a promising therapeutic option for the manage- ment of this condition. Based on populations studied in clinical trials, it seems that the role of sapropterin is best defined in patients with baseline phenylalanine levels greater than 7.5 mg/dL who demonstrate a response to therapy. Therefore, it appears that many patients over age 8 with mild or classic PKU, as well as certain patients with mild HPA, are candidates for a trial course of sapropterin therapy to determine whether they are responders, since a prediction of response is not possible at this time. Although studies have demonstrated a decrease in serum phenylalanine concentration among select patients with PKU, 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 for many 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 define its role in the treatment of PKU. Karly A Hegge PharmD BCPS, Clinical Pharmacist, Falls Com- munity Health; Assistant Professor of Pharmacy Practice, College of Pharmacy, South Dakota State University, Sioux Falls, SD Kristin K Horning PharmD BCPS, Clinical Pharmacist, East Des Moines Family Care Center; Assistant Professor (Clinical), College of Pharmacy, University of Iowa, Des Moines, IA Gregory J Peitz PharmD BCPS, Clinical Pharmacist, Sanford USD Medical Center, Sioux Falls, SD Kassy Hegge MD, Pediatric Resident Physician, Mayo Clinic, Rochester, MN Reprints: Dr. Karly Hegge, College of Pharmacy, South Dakota State University, University Center North, 4801 N. Career Ave., Sioux Falls, SD 57106, fax 605/367-8423, karly.hegge@sdstate.edu Financial disclosure: None reported References 1. National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 1618, 2000. Pedi- atrics 2001;108:972-82. 2. 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Recently-approved sapropterin reduces phenylalanine levels: when diet is not enough, a well known metabolic disorder can now be man- aged better through medication. Managed Care Magazine. March 2008. www.managedcaremag.com/archives/0803/0803.biotech.html (accessed 2009 Jan 31). 45. ClinicalTrials.gov: a service of the US National Institutes of Health. www. clinicaltrials.gov/ct2/results?term=sapropterin (accessed 2009 Jan 31). Sapropterina: Un Agente Teraputico Nuevo Para Fenilcetonuria KA Hegge, KK Horning, GJ Peitz, y K Hegge Ann Pharmacother 2009;43:1466-73. EXTRACTO OBJETIVO: Resumir el papel de la farmacoterapia en el manejo de fenilceto- nuria (FCU) y revisar la farmacologa, farmacocintica, farmacodinmica, datos de eficacia, y perfil de seguridad de sapropterina para esta indicacin. 1472 I The Annals of Pharmacotherapy I 2009 September, Volume 43 theannals.com KA Hegge et al. at Univ Catolica Andres Bello on July 4, 2014 aop.sagepub.com Downloaded from Sapropterin: A New Therapeutic Agent for Phenylketonuria The Annals of Pharmacotherapy I 2009 September, Volume 43 I 1473 theannals.com FUENTES DE INFORMACIN: Se llev a cabo una bsqueda de literatura usando MEDLINE (1966mayo 2009), Extractos Farmacuticos Internacionales (1970mayo 2009), y base de datos Cochrane (2008) para las siguientes palabras claves: sapropterina, tetrahidrobiopterina, fenilcetonurias, y fenilalanina. SELECCIN DE FUENTES DE INFORMACIN Y MTODO DE EXTRACCIN DE INFORMACIN: Se revisaron estudios en humanos publicados en el idioma ingls los cuales examinaron el papel de tetrahidrobiopterina (BH4) en el manejo de FCU para evaluar la farmacologa, farmacocintica, farma- codinmica, datos de eficacia, y perfil de seguridad de sapropterina. Todos los estudios controlados aleatorios fase 2 y 3 que evaluaron la seguridad y eficacia de sapropterina fueron incluidos en esta evaluacin de la literatura. SNTESIS: La sapropterina representa el nico frmaco aprobado por la Administracin de Drogas y Alimentos para FCU que responde a BH4, lo que marca un avance importante en el tratamiento de esta condicin. La sapropterina puede aumentar la actividad de la enzima hidroxilasa de fenilalanina para disminuir las concentraciones sricas de fenilalanina en los pacientes con hiperfenilalaninemia y alguna funcin residual de esta enzima. La sapropterina ha sido comparada a placebo en un estudio fase 2 y otro fase 3 demostrando una respuesta significativamente mejor. Este agente parece ser seguro y bien tolerado con una incidencia de eventos adversos similar a placebo basado en los estudios disponibles. Sin embargo, se necesitan estudios adicionales para evaluar la seguridad y eficacia a largo plazo de la terapia de sapropterina. CONCLUSIONES: La sapropterina ofrece una opcin teraputica prometedora para individuos selectos con FCU que responde a BH4, aunque los datos a largo plazo evaluando su seguridad y eficacia en escenarios de prctica clnica tradicionales son limitados. Se recomienda que los clnicos deben tomar en cuenta factores como costo y la adherencia del paciente al medicamento y/o dieta cuando se considere la terapia de sapropterina. Traducido por Juan F Feli Saproptrine: un Nouvel Agent Thrapeutique pour le Traitement de la Phnylctonurie KA Hegge, KK Horning, GJ Peitz, et K Hegge Ann Pharmacother 2009;43:1466-73. RSUM OBJECTIF: Rsumer le rle de la pharmacothrapie dans la prise en charge de la phnylctonurie et revoir la pharmacologie, la pharmacocintique, la pharmacodynamie, les donnes defficacit, et le profil dinnocuit de la saproptrine pour cette indication. REVUE DE LA LITTRATURE: Une recherche de la littrature a t faite dans les banques de donnes informatise MEDLINE (1966mai 2009), International Pharmaceutique Rsum (1970mai 2009), et Cochrane (2008) laide des mots-cl suivants: saproptrine, ttrahydrobioptrine, phnylctonurie, et phnylalanine. SLECTION DES TUDES ET DE LINFORMATION: Les tudes chez lhumain publies en langue anglaise et concernant le rle de la ttrabioptrine (BH4) pour le traitement de la phnylctonurie ont t revues afin dvaluer la pharmacologie, la pharmacocintique, la pharmacodynamie, les donnes defficacit, et le profil dinnocuit de la saproptrine. Toutes les tudes de phase 2 et 3, randomises et contrles, valuant linnocuit et lefficacit de la saproptrine ont t incluses dans cette valuation de la littrature. RSUM: La saproptrine reprsente le seul mdicament approuv par la FDA pour le traitement de la phnylctonurie rpondant au BH4, marquant ainsi une importante avance dans le traitement de cette condition. Chez les individus prsentant une hyperphnylalaninmie et une activit rsiduelle de la phnylalanine hydroxylase, la saproptrine peut augmenter lactivit de cette enzyme et permettre de diminuer davantage les concen- trations sriques de phnylalanine. La saproptrine a t compare un placebo dans un essai clinique de phase 2 et un autre de phase 3, celle-ci dmontrant de meilleurs taux de rponse. En se basant sur les donnes des tudes disponibles, cet agent semble scuritaire et bien tolr, prsentant un taux deffets indsirables semblable celui du placebo. Cependant, dautres tudes sont ncessaires afin dvaluer linnocuit et lefficacit long terme de la saproptrine. CONCLUSIONS: La saproptrine offre une option thrapeutique prometteuse pour certains individus prsentant une phnylctonurie qui rpond au BH4, mme si des donnes long terme valuant son innocuit et son efficacit dans un cadre de pratique clinique sont manquantes. Lorsque le clinicien envisage un traitement par la saproptrine, dautres facteurs comme le cot du traitement et ladhsion du patient au traitement et la dite doivent aussi tre pris en compte. Traduit par Denyse Demers at Univ Catolica Andres Bello on July 4, 2014 aop.sagepub.com Downloaded from