The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin):: a phase II, multicentre, open-label, screening study

被引:134
作者
Burton, B. K.
Grange, D. K.
Milanowski, A.
Vockley, G.
Feillet, F.
Crombez, E. A.
Abadie, V.
Harding, C. O.
Cederbaum, S.
Dobbelaere, D.
Smith, A.
Dorenbaum, A.
机构
[1] Northwestern Univ, Childrens Mem Hosp, Feinberg Sch Med, Div Genet, Chicago, IL 60614 USA
[2] Washignton Sch Med, St Louis Childrens Hosp, St Louis, MO USA
[3] Inst Matki & Dziecka, Warsaw, Poland
[4] Hop Enfants, Dept Pediat, Vandoeuvre Les Nancy, France
[5] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA USA
[6] Hop Necker Enfants Malad Pediat Gen, Paris, France
[7] Oregon Hlth & Sci Univ, Portland, OR 97201 USA
[8] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA
[9] CHRU Lille, Hop Jeanne Flandres, Lille, France
[10] Pacific Data Designs, San Francisco, CA USA
[11] BioMarin Pharmaceut Inc, Novato, CA USA
关键词
D O I
10.1007/s10545-007-0605-z
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
This study aimed to evaluate the response to and safety of an 8-day course of sapropterin dihydrochloride (6R-tetrahydrobiopterin or 6R-BH4) 10 mg/kg per day in patients with phenylketonuria (PKU), who have elevated blood phenylalanine (Phe) levels, and to identify a suitable cohort of patients who would respond to sapropterin dihydrochloride treatment with a reduction in blood Phe level. Eligible patients were aged >= 8 years, had blood Phe levels >= 450 mu mol/L and were not adhering to a Phe-restricted diet. Suitable patients were identified by a >= 30% reduction in blood Phe level from baseline to day 8 following sapropterin dihydrochloride treatment. The proportion of patients who met these criteria was calculated for the overall population and by baseline Phe level (< 600, 600 to < 900, 900 to < 1200 and >= 1200 mu mol/L). In total, 485/490 patients completed the study and 20% (96/485) were identified as patients who would respond to sapropterin dihydrochloride. A reduction in Phe level was observed in all subgroups, although response was greater in patients with lower baseline Phe levels. Wide variability in response was seen across all baseline Phe subgroups. The majority of adverse events were mild and all resolved without complications. Sapropterin dihydrochloride was well tolerated and reduced blood Phe levels across all PKU phenotypes tested. Variability in reduction of Phe indicates that the response to sapropterin dihydrochloride cannot be predicted by baseline Phe level.
引用
收藏
页码:700 / 707
页数:8
相关论文
共 19 条
[1]   High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: a study of 1919 patients observed from 1988 to 2002 [J].
Bernegger, C ;
Blau, N .
MOLECULAR GENETICS AND METABOLISM, 2002, 77 (04) :304-313
[2]   The metabolic and molecular bases of tetrahydroblopterin-responsive phenylalanine hydroxylase deficiency [J].
Blau, N ;
Erlandsen, H .
MOLECULAR GENETICS AND METABOLISM, 2004, 82 (02) :101-111
[3]   Long-term follow-up of a patient with mild tetrahydrobiopterin-responsive phenylketonuria [J].
Cerone, R ;
Schiaffino, MC ;
Fantasia, AR ;
Perfumo, M ;
Moller, LB ;
Blau, N .
MOLECULAR GENETICS AND METABOLISM, 2004, 81 (02) :137-139
[4]   Extended tetrahydrobiopterin loading test in the diagnosis of cofactor-responsive phenylketonuria:: A pilot study [J].
Fiege, B ;
Bonafé, L ;
Ballhausen, D ;
Baumgartner, M ;
Thöny, B ;
Meili, D ;
Fiori, L ;
Giovannini, M ;
Blau, N .
MOLECULAR GENETICS AND METABOLISM, 2005, 86 :S91-S95
[5]  
Grier Robert E, 2004, Genet Med, V6, P66, DOI 10.1097/01.GIM.0000106163.35058.7D
[6]   Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria [J].
Hennermann, JB ;
Bührer, C ;
Blau, N ;
Vetter, B ;
Mönch, E .
MOLECULAR GENETICS AND METABOLISM, 2005, 86 :S86-S90
[7]   EFFECT OF AGE AT LOSS OF DIETARY CONTROL ON INTELLECTUAL-PERFORMANCE AND BEHAVIOR OF CHILDREN WITH PHENYLKETONURIA [J].
HOLTZMAN, NA ;
KRONMAL, RA ;
VANDOORNINCK, W ;
AZEN, C ;
KOCH, R .
NEW ENGLAND JOURNAL OF MEDICINE, 1986, 314 (10) :593-598
[9]   Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency [J].
Kure, S ;
Hou, DC ;
Ohura, T ;
Iwamoto, H ;
Suzuki, S ;
Sugiyama, N ;
Sakamoto, O ;
Fujii, K ;
Matsubara, Y ;
Narisawa, K .
JOURNAL OF PEDIATRICS, 1999, 135 (03) :375-378
[10]  
LEVY H, 2007, AM COLL MED GEN