title: Pharmacokinetics of sapropterin in patients with phenylketonuria.
abstract: OBJECTIVE
  Untreated phenylketonuria is characterized by neurocognitive and neuromotor impairment, which result from elevated blood phenylalanine concentrations. To date, the recommended management of phenylketonuria has been the use of a protein-restricted diet and the inclusion of phenylalanine-free protein supplements; however, this approach is often associated with poor compliance and a suboptimal clinical outcome. Sapropterin dihydrochloride, herein referred to as sapropterin, a synthetic formulation of 6R-tetrahydrobiopterin (6R-BH4), has been shown to be effective in reducing blood phenylalanine concentrations in patients with phenylketonuria. The objective of the current study was to characterize the pharmacokinetics and pharmacokinetic variability of sapropterin and to identify the characteristics that influence this variability.
  
  
  METHODS
  This was a 12-week, fixed-dose phase of an open-label extension study. The study was conducted at 26 centres in North America and Europe.Patients with phenylketonuria were eligible to participate if they were > or =8 years of age and had received > or =80% of the scheduled doses in a previous 6-week, randomized, placebo-controlled study or had been withdrawn from that study after exceeding a plasma phenylalanine concentration of > or =1500 micromol/L to > or =1800 micromol/L, depending on the subject's age and baseline plasma phenylalanine concentration. A total of 78 patients participated. Patients received oral once-daily doses of sapropterin (Kuvan) 5, 10 or 20 mg/kg/day. Blood samples for the pharmacokinetic analysis were obtained during weeks 6, 10 and 12. A D-optimal sparse sampling strategy was used, and data were analysed by population-based, nonlinear, mixed-effects modelling methods.
  
  
  METHODS
  In a prospectively planned analysis, the apparent clearance, apparent volume of distribution, absorption rate constant and associated interindividual variabilities of each parameter were estimated by modelling observed BH4 plasma concentration-time data.
  
  
  RESULTS
  The best structural model to describe the pharmacokinetics of sapropterin was a two-compartment model with first-order input, first-order elimination and a baseline endogenous BH4 concentration term. Total bodyweight was the only significant covariate identified, the inclusion of which on both the apparent clearance (mean = 2100 L/h/70 kg) and central volume of distribution (mean = 8350 L/70 kg) substantially improved the model's ability to describe the data. The mean (SD) terminal half-life of sapropterin was 6.69 (2.29) hours and there was little evidence of accumulation, even at the highest dose.
  
  
  CONCLUSIONS
  These findings, taken together with the observed therapeutic effect, support bodyweight-based, once-daily dosing of sapropterin 5-20 mg/kg/day.
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital d'Enfants, CHU Brabois, Vandoeuvre les Nancy, France. f.feillet@chu-nancy.fr
authors.forename: François
authors.initials: F
authors.lastname: Feillet
authors.forename: Lorne
authors.initials: L
authors.lastname: Clarke
authors.forename: Concetta
authors.initials: C
authors.lastname: Meli
authors.forename: Mark
authors.initials: M
authors.lastname: Lipson
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Morris
authors.forename: Paul
authors.initials: P
authors.lastname: Harmatz
authors.forename: Diane R
authors.initials: DR
authors.lastname: Mould
authors.forename: Bruce
authors.initials: B
authors.lastname: Green
authors.forename: Alex
authors.initials: A
authors.lastname: Dorenbaum
authors.forename: Marcello
authors.initials: M
authors.lastname: Giovannini
authors.forename: Erik
authors.initials: E
authors.lastname: Foehr
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D001835:Body Weight / Q000187:drug effects; D002648:Child; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005060:Europe; D005260:Female; D005500:Follow-Up Studies; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010649:Phenylalanine / Q000097:blood; D010661:Phenylketonurias / Q000097:blood / Q000188:drug therapy*; D014481:United States; D055815:Young Adult
chemical_list: D001708:Biopterins; D010649:Phenylalanine; D003404:Creatinine; C003402:sapropterin