title: Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial.
abstract: Sapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children <4 years.
  
  
  
  In total, 109 male or female children <4 years with confirmed BH4-responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7-42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters.
  
  
  
  The addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH4-responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, sapropterin has received EU approval to treat patients <4 years with BH4-responsive phenylketonuria.
  
  
  
  ClinicalTrials.gov, NCT01376908 . Registered June 17, 2011.
authors.affiliation: University Children's Hospital, University Medical Center Hamburg Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany. muntau@uke.de.
authors.forename: Ania C
authors.initials: AC
authors.lastname: Muntau
authors.affiliation: University Hospital, Padova, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Burlina
authors.affiliation: Universitair Ziekenhuis Antwerpen, Antwerp, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Eyskens
authors.affiliation: Children's Hospital Kreiskliniken, Reutlingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Freisinger
authors.affiliation: Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium.
authors.forename: Corinne
authors.initials: C
authors.lastname: De Laet
authors.affiliation: Universita La Sapienza, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leuzzi
authors.affiliation: Muenster University Children's Hospital, Muenster, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Rutsch
authors.affiliation: Hacettepe University School of Medicine, Ankara, Turkey.
authors.forename: H Serap
authors.initials: HS
authors.lastname: Sivri
authors.affiliation: Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Suresh
authors.initials: S
authors.lastname: Vijay
authors.affiliation: Department of Pediatrics, University of Bologna, Bologna, Italy.
authors.forename: Milva Orquidea
authors.initials: MO
authors.lastname: Bal
authors.affiliation: Centre for Paediatric and Adolescent Medicine, Division for Neuropaediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany.
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Gramer
authors.affiliation: University Children's Hospital, Prague, Czech Republic.
authors.forename: Renata
authors.initials: R
authors.lastname: Pazdírková
authors.affiliation: Great Ormond Street Hospital, London, UK.
authors.forename: Maureen
authors.initials: M
authors.lastname: Cleary
authors.affiliation: Dr. von Hauner Children's Hospital, Munich, Germany.
authors.forename: Amelie S
authors.initials: AS
authors.lastname: Lotz-Havla
authors.affiliation: Merck Institute for Pharmacometrics, Lausanne, Switzerland.
authors.forename: Alain
authors.initials: A
authors.lastname: Munafo
authors.affiliation: Projections Research Inc., Phoenixville, USA.
authors.forename: Diane R
authors.initials: DR
authors.lastname: Mould
authors.affiliation: EMD Serono, Billerica, MA, USA.
authors.forename: Flavie
authors.initials: F
authors.lastname: Moreau-Stucker
authors.affiliation: EMD Serono, Billerica, MA, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rogoff
mesh_terms: D000465:Algorithms; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D002675:Child, Preschool; D004032:Diet / Q000379:methods; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010649:Phenylalanine / Q000008:administration & dosage / Q000097:blood; D010651:Phenylalanine Hydroxylase / Q000378:metabolism; D010661:Phenylketonurias / Q000097:blood / Q000178:diet therapy* / Q000188:drug therapy*
chemical_list: D001708:Biopterins; D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase; C003402:sapropterin
keywords: Hyperphenylalaninemia; Pharmacokinetics; Phenylalanine hydroxylase; Phenylketonuria; SPARK; Sapropterin