title: A prospective population pharmacokinetic analysis of sapropterin dihydrochloride in infants and young children with phenylketonuria.
abstract: OBJECTIVE
  Untreated phenylketonuria (PKU), a hereditary metabolic disorder caused by a genetic mutation in phenylalanine hydroxylase (PAH), is characterized by elevated blood phenylalanine (Phe) and severe neurologic disease. Sapropterin dihydrochloride, a synthetic preparation of naturally occurring PAH cofactor tetrahydrobiopterin (BH4), activates residual PAH in a subset of patients, resulting in decreased blood Phe and increased Phe tolerance. The objective of this study was to determine the appropriate dose of sapropterin in pediatric patients (0-6 years). The study design used D-optimization and was prospectively powered to achieve precise estimates of clearance and volume of distribution.
  
  
  METHODS
  Oral sapropterin (5 or 20 mg/kg) was administered once daily. Sapropterin plasma concentrations were measured by a validated method. Population pharmacokinetic analysis was performed with NONMEM(®) version 7.2 on pooled data from 156 pediatric and adult PKU patients in two phase III clinical studies.
  
  
  RESULTS
  The best pharmacokinetic model was a one-compartment model with an absorption lag, first-order input, and linear elimination, with a factor describing endogenous BH4 levels. Body weight was the only covariate significantly affecting sapropterin pharmacokinetics. Based on recommended dosing, exposure across age groups was comparable. The absorption rate and terminal half-life suggest flip-flop pharmacokinetic behavior where absorption is rate limiting.
  
  
  CONCLUSIONS
  The effect of weight on sapropterin pharmacokinetics was significant and exposure was comparable across age groups; thus, weight-based dosing is appropriate. The doses selected for pediatric patients provided similar exposure as in adults. Given the slow absorption and elimination half-life, once-daily dosing is justified.
authors.affiliation: BioMarin Pharmaceutical Inc., 105 Digital Dr., 94949, Novato, CA, USA, yqi@bmrn.com.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Qi
authors.forename: Diane R
authors.initials: DR
authors.lastname: Mould
authors.forename: Huiyu
authors.initials: H
authors.lastname: Zhou
authors.forename: Markus
authors.initials: M
authors.lastname: Merilainen
authors.forename: Donald G
authors.initials: DG
authors.lastname: Musson
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D017326:Clinical Trials, Phase III as Topic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D015337:Multicenter Studies as Topic; D010661:Phenylketonurias / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D001708:Biopterins; C003402:sapropterin