Relationship Between Serum Concentrations of Nitisinone and Its Effect on Homogentisic Acid and Tyrosine in Patients with Alkaptonuria

  • Birgitta OlssonEmail author
  • Trevor F Cox
  • Eftychia E Psarelli
  • Johan Szamosi
  • Andrew T Hughes
  • Anna M Milan
  • Anthony K Hall
  • Jozef Rovensky
  • Lakshminarayan R Ranganath
Research Report
Part of the JIMD Reports book series (JIMD, volume 24)


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.

Objectives: 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.

Method: 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 [Cmax]) 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.

Conclusion: 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.


Homogentisic Acid Tyrosine Concentration Hereditary Tyrosinemia Hereditary Tyrosinemia Type Predose Serum 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We wish to thank Jean Devine and Jeannette Usher in the Clinical Biochemistry and Metabolic Medicine for the handling of the serum and urine samples. We also want to thank Helen Bygott, Emily Luangrath-Nicholson, Richard Fitzgerald, and Asad Ullah at the Clinical Trials Units in Royal Liverpool University Hospital and Oľga Lukačová, Eva Vrtíková, and Vanda Mlynariková in the National Institute of Rheumatic Disease in Piešťany for the diligence shown in carrying out the study.

This study was part of the DevelopAKUre program, which received funding from the European Commission 7th Framework Program (FP7).

Supplementary material

346908_1_En_412_MOESM1_ESM.docx (111 kb)
Figure S1. Mean (SD) steady-state serum concentrations of nitisinone in AKU patients (N = 8 per dose group)
346908_1_En_412_MOESM2_ESM.docx (92 kb)
Figure S2. Mean (SD) serum concentrations of HGA and tyrosine in AKU patients before treatment with nitisinone (N = 32)


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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Birgitta Olsson
    • 1
    Email author
  • Trevor F Cox
    • 2
  • Eftychia E Psarelli
    • 2
  • Johan Szamosi
    • 1
  • Andrew T Hughes
    • 3
  • Anna M Milan
    • 3
  • Anthony K Hall
    • 4
  • Jozef Rovensky
    • 5
  • Lakshminarayan R Ranganath
    • 3
  1. 1.Swedish Orphan Biovitrum AB (publ)StockholmSweden
  2. 2.Cancer Research UK Liverpool Cancer Trials UnitUniversity of LiverpoolLiverpoolUK
  3. 3.Department of Clinical Biochemistry and Metabolic MedicineRoyal Liverpool University Hospital TrustLiverpoolUK
  4. 4.Cudos BVHoofddorpThe Netherlands
  5. 5.National Institute of Rheumatic DiseasesPiešťanySlovakia

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