Advertisement

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)

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.

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.

Keywords

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.

Notes

Acknowledgements

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)

References

  1. Anikster Y, Nyhan WL, Gahl WA (1998) NTBC and alkaptonuria. Am J Hum Genet 63:920–921PubMedCentralCrossRefPubMedGoogle Scholar
  2. Davison AS, Milan AM, Hughes AT et al (2014) Serum concentrations and urinary excretion of homogentisic acid and tyrosine in normal subjects. Clin Chem Lab Med. doi: 10.1515/cclm-2014-0668 Google Scholar
  3. Ellis MK, Whitfield AC, Gowans LA et al (1995) Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione and 2-(2-chloro-4-methanesulfonylbenzoyl)-cyclohexane-1,3-dione. Toxicol Appl Pharmacol 133:12–19CrossRefPubMedGoogle Scholar
  4. Garrod AE (1902) About alkaptonuria. Med Chir Trans 85:69–78PubMedCentralPubMedGoogle Scholar
  5. Gough K, Hutchison M, Keene O et al (1995) Assessment of dose proportionality: report from the statisticians in the pharmaceutical industry/pharmaceutics UK joint working party. Drug Inf J 29:1039–1048Google Scholar
  6. Hall MG, Wilks MF, Provan WM et al (2001) Pharmacokinetics and pharmacodynamics of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione, inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteers. Br J Clin Pharmacol 52:169–177PubMedCentralCrossRefPubMedGoogle Scholar
  7. Hanhart E (1947) Neue sonderformen von keratosis palmo-plantaris, u.a. eine regelmässig-dominante mit systematisierten lipomen, ferner 2 einfach-rezessive mit schwachsinn und z.T. mit hornhautveränderungen des auges (ektodermalsyndrom). Dermatologica 94:286–308CrossRefPubMedGoogle Scholar
  8. Hughes AT, Milan AM, Christensen P et al (2014) Urine homogentisic acid and tyrosine: simultaneous analysis by liquid chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 963:106–112. doi: 10.1016/j.jchromb.2014.06.002
  9. Hughes AT, Milan AM, Davison AS et al (2015) Serum markers in alkaptonuria: simultaneous analysis of homogentisic acid, tyrosine and nitisinone by liquid chromatography tandem mass spectrometry. Ann Clin Biochem pii:0004563215571969Google Scholar
  10. Introne WJ, Phornphutkul C, Bernardini I et al (2002) Exacerbation of the ochronosis of alkaptonuria due to renal insufficiency and improvement after renal transplantation. Mol Genet Metab 77:136–142CrossRefPubMedGoogle Scholar
  11. Introne WJ, Perry MB, Troendle J et al (2011) A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab 103:307–314PubMedCentralCrossRefPubMedGoogle Scholar
  12. Lindstedt S, Holme E, Lock EA et al (1992) Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet 340:813–817CrossRefPubMedGoogle Scholar
  13. Lock E, Ranganath LR, Timmis O (2014) The role of nitisinone in tyrosine pathway disorders. Curr Rheumatol Rep 16:457CrossRefPubMedGoogle Scholar
  14. Lustberg TJ, Schulman JD, Seegmiller JE (1969) Metabolic fate of homogentisic acid-1–14 C (HGA) in alkaptonuria and effectiveness of ascorbic acid in preventing experimental ochronosis. Arthritis Rheum 12:678Google Scholar
  15. Mayorandan S, Meyer U, Gokcay G et al (2014) Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice. Orphanet J Rare Dis 9:107PubMedCentralCrossRefPubMedGoogle Scholar
  16. O’Brien WM, La Du BN, Bunim JJ (1963) Biochemical, pathologic and clinical aspects of alcaptonuria, ochronosis and ochronotic arthropathy: review of world literature (1584–1962). Am J Med 34:813–838CrossRefGoogle Scholar
  17. Preston AJ, Keenan CM, Sutherland H et al (2013) Ochronotic osteoarthropathy in a mouse model of alkaptonuria, and its inhibition by nitisinone. Ann Rheum Dis 73(1):284–289CrossRefPubMedGoogle Scholar
  18. Ranganath LR, Jarvis JC, Gallagher JA (2013) Recent advances in management of alkaptonuria (invited review; best practice article). J Clin Pathol 66:367–373CrossRefPubMedGoogle Scholar
  19. Ranganath LR, Milan AM, Hughes AT (2014) Suitability of nitisinone in alkaptonuria 1 (SONIA 1): an international, multicenter, randomized, open-label, no-treatment controlled, parallel-group, dose–response study to investigate the effect of once daily nitisinone on 24-hour urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment. Ann Rheum Dis 1–6. doi: 10.1136/annrheumdis-2014-206033
  20. Suzuki Y, Oda K, Yoshikawa Y et al (1999) A novel therapeutic trial of homogentisic aciduria in a murine model of alkaptonuria. J Hum Genet 44:79–84CrossRefPubMedGoogle Scholar
  21. Zannoni VG, Lomtevas N, Goldfinger S (1969) Oxidation of homogentisic acid to ochronotic pigment in connective tissue. Biochim Biophys Acta 177:94–105CrossRefPubMedGoogle Scholar

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

Personalised recommendations