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 [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.
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.
Competing interests: None declared
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Anikster Y, Nyhan WL, Gahl WA (1998) NTBC and alkaptonuria. Am J Hum Genet 63:920–921
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
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 133:12–19
Garrod AE (1902) About alkaptonuria. Med Chir Trans 85:69–78
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 29:1039–1048
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 52:169–177
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 94:286–308
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
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:0004563215571969
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 77:136–142
Introne WJ, Perry MB, Troendle J et al (2011) A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab 103:307–314
Lindstedt S, Holme E, Lock EA et al (1992) Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet 340:813–817
Lock E, Ranganath LR, Timmis O (2014) The role of nitisinone in tyrosine pathway disorders. Curr Rheumatol Rep 16:457
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 12:678
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 9:107
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 34:813–838
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):284–289
Ranganath LR, Jarvis JC, Gallagher JA (2013) Recent advances in management of alkaptonuria (invited review; best practice article). J Clin Pathol 66:367–373
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
SmPC for Orfadin capsules. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000555/WC500049195.pdf
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 44:79–84
Zannoni VG, Lomtevas N, Goldfinger S (1969) Oxidation of homogentisic acid to ochronotic pigment in connective tissue. Biochim Biophys Acta 177:94–105
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).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Ertan Mayatepek, MD
Synopsis (Take-Home Message)
In patients with alkaptonuria, nitisinone decreases urinary excretion of HGA in a concentration-dependent manner, while the increase in serum tyrosine is less clearly related to nitisinone concentrations.
Compliance with Ethics Guidelines
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (6).
Informed consent was obtained from all patients before being included in the study.
Animal rights: Not applicable for this clinical study.
The study EudraCT number is 2012-005340-24 and is registered at ClinicalTrials.gov with number NCTO1828463 and the title “Dose Response Study of Nitisinone in Alkaptonuria (SONIA1).”
Conflict of Interest
B Olsson and J Szamosi are Sobi employees and shareholders. All other authors declare that they have no conflict of interest.
Contributors
BO, LRR, AKH, TFC, JR contributed to the study design.
LRR, JR undertook medical procedures.
ATH, AMA developed analytical methods and analyzed study samples.
TFC, EEP, JS, BO contributed to the statistical analyses including PK calculations.
BO drafted the first version of the manuscript.
All authors contributed to the interpretation of data and writing and revision of the manuscript.
All authors approved the manuscript for publication.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Rights and permissions
Copyright information
© 2015 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Olsson, B. et al. (2015). Relationship Between Serum Concentrations of Nitisinone and Its Effect on Homogentisic Acid and Tyrosine in Patients with Alkaptonuria. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 24. JIMD Reports, vol 24. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_412
Download citation
DOI: https://doi.org/10.1007/8904_2015_412
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-48226-1
Online ISBN: 978-3-662-48227-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)