P

henylketonuria (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 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 (1966–May
2009), International Pharmaceutical Abstracts (1970–May 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
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Sapropterin: A New Therapeutic Agent for Phenylketonuria
Karly A Hegge, Kristin K Horning, Gregory J Peitz, and Kassy Hegge
Formulary Forum

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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 2.5–10 mg/dL), mild PKU (phenylalanine
concentration 10–20 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
patient’s 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
agent’s appropriate place in therapy. With the Food and
Drug Administration’s (FDA’s) 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
(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 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.
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Figure 1. The metabolism of phenylalanine.
3
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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 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 (10–33
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 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 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 (0–10 h)
(AUC
0-10 h
) was 1.6-fold greater with 20 mg/kg compared
with 10 mg/kg (0.0508 vs 0.0326 mg•h/dL). When given
sublingually at 2 mg/kg, plasma concentrations of 6R-BH4
were 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, AUC
0-32 h
0.617 mg•h/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 8–24
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
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Table 1. National Institutes of Health Target
Phenylalanine Concentrations
1,a
Goal Phenylalanine
Subjects Level (mg/dL)
≤12 y of age or pregnant 2–6
>12 y of age if not pregnant 2–10
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
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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 1–2 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-
BH4–responsive 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-BH4–responsive 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
8–12 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
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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.
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et al.
40
reported successful treatment of 2 infants with mild
PKU using BH4 10–20 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 manufacturer’s 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 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 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 5–20 mg/kg once daily.
17
Sapropterin is supplied as a 100-mg tablet, which should
be dissolved into 120–240 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
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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.
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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 drug’s 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
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phenylketonuria: screening and management, October 16–18, 2000. Pedi-
atrics 2001;108:972-82.
2. Mabry-Hernandez I, Wolff T, Green K. Screening for phenylketonuria
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Sapropterina: Un Agente Terapéutico 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 farmacología, farmacocinética, farmacodinámica,
datos de eficacia, y perfil de seguridad de sapropterina para esta indicación.
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Sapropterin: A New Therapeutic Agent for Phenylketonuria
The Annals of Pharmacotherapy
I
2009 September, Volume 43
I
1473 theannals.com
FUENTES DE INFORMACIÓN: Se llevó a cabo una búsqueda de literatura
usando MEDLINE (1966–mayo 2009), Extractos Farmacéuticos
Internacionales (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 idioma
inglés los cuales examinaron el papel de tetrahidrobiopterina (BH4) en
el 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 la
seguridad y eficacia de sapropterina fueron incluidos en esta evaluación
de la literatura.
SÍNTESIS: La sapropterina representa el único fármaco aprobado por la
Administración 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 de
fenilalanina para disminuir las concentraciones séricas de fenilalanina en
los pacientes con hiperfenilalaninemia y alguna función 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 opción terapéutica prometedora
para individuos selectos con FCU que responde a BH4, aunque los datos
a largo plazo evaluando su seguridad y eficacia en escenarios de práctica
clínica tradicionales son limitados. Se recomienda que los clínicos 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 Feliú
Saproptérine: un Nouvel Agent Thérapeutique pour le Traitement de
la Phénylcétonurie
KA Hegge, KK Horning, GJ Peitz, et K Hegge
Ann Pharmacother 2009;43:1466-73.
RÉSUMÉ
OBJECTIF: Résumer le rôle de la pharmacothérapie dans la prise en charge
de la phénylcétonurie et revoir la pharmacologie, la pharmacocinétique,
la pharmacodynamie, les données d’efficacité, et le profil d’innocuité de
la saproptérine pour cette indication.
REVUE DE LA LITTÉRATURE: Une recherche de la littérature a été faite dans
les 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’humain
publiées en langue anglaise et concernant le rôle de la tétrabioptérine
(BH4) pour le traitement de la phénylcétonurie ont été revues afin
d’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, évaluant
l’innocuité et l’efficacité de la saproptérine ont été incluses dans cette
évaluation de la littérature.
RÉSUMÉ: La saproptérine représente le seul médicament approuvé par la
FDA pour le traitement de la phénylcétonurie répondant au BH4, marquant
ainsi une importante avancée dans le traitement de cette condition. Chez
les individus présentant une hyperphénylalaninémie et une activité
résiduelle de la phénylalanine hydroxylase, la saproptérine peut augmenter
l’activité de cette enzyme et permettre de diminuer davantage les concen-
trations sériques de phénylalanine. La saproptérine a été comparée à un
placebo dans un essai clinique de phase 2 et un autre de phase 3, celle-ci
démontrant de meilleurs taux de réponse. En se basant sur les données
des 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 et
l’efficacité à long terme de la saproptérine.
CONCLUSIONS: La saproptérine offre une option thérapeutique prometteuse
pour certains individus présentant une phénylcétonurie qui répond au
BH4, même si des données à long terme évaluant son innocuité et son
efficacité dans un cadre de pratique clinique sont manquantes. Lorsque
le clinicien envisage un traitement par la saproptérine, d’autres facteurs
comme le coût du traitement et l’adhésion du patient au traitement et à la
diète doivent aussi être pris en compte.
Traduit par Denyse Demers
at Univ Catolica Andres Bello on July 4, 2014 aop.sagepub.com Downloaded from

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