title: Relationship Between Serum Concentrations of Nitisinone and Its Effect on Homogentisic Acid and Tyrosine in Patients with Alkaptonuria.
abstract: BACKGROUND
  Alkaptonuria (AKU) is a serious genetic disease due to a defect in tyrosine metabolism, leading to increased serum levels of homogentisic acid (HGA). Nitisinone decreases HGA in AKU, but the concentration-response relationship has not been previously reported.
  
  
  OBJECTIVE
  To determine the relationship between serum concentrations of nitisinone and the effect on both HGA and tyrosine; secondly to determine steady-state pharmacokinetics of nitisinone in AKU patients.
  
  
  METHODS
  Thirty-two patients with AKU received either 1, 2, 4, or 8 mg nitisinone daily. Urine and serum HGA and serum tyrosine and nitisinone were measured during 24 h at baseline (before first dose) and after 4 weeks of treatment.
  
  
  RESULTS
  Nitisinone pharmacokinetics (area under the curve [AUC] and maximum concentrations [C max]) were dose proportional. The median oral clearance determined in all patients, irrespective of dose, was 3.18 mL/h·kg (range 1.6-6.7).Nitisinone decreased urinary excretion of HGA in a concentration-dependent manner, with a maximum effect seen at average nitisinone concentrations of 3 μmol/L. The association between nitisinone and tyrosine concentrations was less pronounced. Serum levels of HGA at Week 4 were below the limit of quantitation in 65% of samples, which prevented determination of the relationship with nitisinone concentrations.
  
  
  CONCLUSIONS
  Nitisinone exhibits dose-proportional pharmacokinetics in the studied dosage interval. Urinary excretion of HGA decreases in a concentration-dependent manner, while the increase in tyrosine is less clearly related to nitisinone concentrations.
authors.affiliation: Swedish Orphan Biovitrum AB (publ), Tomtebodavägen 23A, SE-112 76, Stockholm, Sweden. birgitta.olsson@sobi.com.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Olsson
authors.affiliation: Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool, 1-3 Brownlow Street, Liverpool, L69 3GL, UK.
authors.forename: Trevor F
authors.initials: TF
authors.lastname: Cox
authors.affiliation: Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool, 1-3 Brownlow Street, Liverpool, L69 3GL, UK.
authors.forename: Eftychia E
authors.initials: EE
authors.lastname: Psarelli
authors.affiliation: Swedish Orphan Biovitrum AB (publ), Tomtebodavägen 23A, SE-112 76, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Szamosi
authors.affiliation: Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital Trust, Prescot Street, Liverpool, L7 8XP, UK.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hughes
authors.affiliation: Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital Trust, Prescot Street, Liverpool, L7 8XP, UK.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Milan
authors.affiliation: Cudos BV, Planetenweg 5, 2132 HN, Hoofddorp, The Netherlands.
authors.forename: Anthony K
authors.initials: AK
authors.lastname: Hall
authors.affiliation: National Institute of Rheumatic Diseases, Nabrezie, Ivana Krasku 4, SK-921 01, Piešťany, Slovakia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Rovensky
authors.affiliation: Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital Trust, Prescot Street, Liverpool, L7 8XP, UK.
authors.forename: Lakshminarayan R
authors.initials: LR
authors.lastname: Ranganath