title: Population pharmacokinetics and pharmacodynamics of cysteamine in nephropathic cystinosis patients.
abstract: BACKGROUND
  Nephropathic cystinosis is an autosomal recessive disorder resulting in an impaired transport of cystine trough the lysosomal membrane causing an accumulation of free cystine in lysosomes. The only specific treatment for nephropathic cystinosis is cysteamine bitartrate. This study was aimed to describe the relationship between cysteamine plasma concentrations and white blood cell cystine levels, and to simulate an optimized administration scheme to improve the management of patients with cystinosis.
  
  
  METHODS
  Cysteamine and cystine concentrations were measured in 69 nephropathic cystinosis patients. A total of 250 cysteamine plasma concentrations and 243 intracellular cystine concentrations were used to perform a population pharmacokinetic and pharmacodynamic analysis. An optimized administration scheme was simulated in order to maintain cystine levels below 1 nmol half-cystine/mg of protein and to investigate the possibility of administrating the treatment less than 4 times a day (QID, recommended). The current dosing recommendations are 1.3 g/m2/day for less than 50 kg BW and 2 g/day thereafter; the maximum dose should not exceed 1.95 g/m2/day.
  
  
  RESULTS
  Cysteamine concentrations were satisfactorily described by a one-compartment model. Parameter estimates were standardized for a mean standard bodyweight using an allometric model. WBC cystine levels were adequately described by an indirect response model where the first-order removal rate constant is stimulated by the cysteamine concentrations.
  
  
  CONCLUSIONS
  According to simulations, in order to increase the percentage of patient with cystine levels below 1 nmol half-cystine/mg of protein, the current dosages could be changed as follows: 80 mg/kg/day (QID) from 10 to 17 kg, 70 mg/kg/day (QID) from 17 to 25 kg, 60 mg/kg/day (QID) from 25 to 40 kg and 50 mg/kg/day (QID) from 40 to 70 kg (these dosages remain under the maximum recommended dose). However an 8-hourly daily treatment (TID) did not provide acceptable cystine levels and should not be proposed.
authors.affiliation: EA 3620, Université Paris Descartes, Sorbonne Paris Cité, France. naim.bouazza@cch.aphp.fr
authors.forename: Naïm
authors.initials: N
authors.lastname: Bouazza
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Tréluyer
authors.forename: Chris
authors.initials: C
authors.lastname: Ottolenghi
authors.forename: Saik
authors.initials: S
authors.lastname: Urien
authors.forename: Georges
authors.initials: G
authors.lastname: Deschenes
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricquier
authors.forename: Patrick
authors.initials: P
authors.lastname: Niaudet
authors.forename: Bernadette
authors.initials: B
authors.lastname: Chadefaux-Vekemans
mesh_terms: D000293:Adolescent; D000328:Adult; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D003543:Cysteamine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003553:Cystine / Q000097:blood; D003554:Cystinosis / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005198:Fanconi Syndrome; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009404:Nephrotic Syndrome / Q000188:drug therapy*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D011837:Radiation-Protective Agents; D003553:Cystine; D003543:Cysteamine