Birgitta Olsson1, Trevor F Cox2, Eftychia E Psarelli2, Johan Szamosi3, Andrew T Hughes4, Anna M Milan4, Anthony K Hall5, Jozef Rovensky6, Lakshminarayan R Ranganath4. 1. Swedish Orphan Biovitrum AB (publ), Tomtebodavägen 23A, SE-112 76, Stockholm, Sweden. birgitta.olsson@sobi.com. 2. Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool, 1-3 Brownlow Street, Liverpool, L69 3GL, UK. 3. Swedish Orphan Biovitrum AB (publ), Tomtebodavägen 23A, SE-112 76, Stockholm, Sweden. 4. Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital Trust, Prescot Street, Liverpool, L7 8XP, UK. 5. Cudos BV, Planetenweg 5, 2132 HN, Hoofddorp, The Netherlands. 6. National Institute of Rheumatic Diseases, Nabrezie, Ivana Krasku 4, SK-921 01, Piešťany, Slovakia.
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.
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 AKUpatients. 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.
Authors: A T Hughes; A M Milan; P Christensen; G Ross; A S Davison; J A Gallagher; J J Dutton; L R Ranganath Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2014-06-07 Impact factor: 3.205
Authors: A S Davison; B P Norman; E A Smith; J Devine; J Usher; A T Hughes; M Khedr; A M Milan; J A Gallagher; L R Ranganath Journal: JIMD Rep Date: 2018-05-13
Authors: A S Davison; N Strittmatter; H Sutherland; A T Hughes; J Hughes; G Bou-Gharios; A M Milan; R J A Goodwin; L R Ranganath; J A Gallagher Journal: Metabolomics Date: 2019-04-29 Impact factor: 4.290
Authors: Andrew S Davison; Brendan P Norman; Gordon A Ross; Andrew T Hughes; Milad Khedr; Anna M Milan; James A Gallagher; Lakshminarayan R Ranganath Journal: JIMD Rep Date: 2019-05-31
Authors: L R Ranganath; A M Milan; A T Hughes; A S Davison; M Khedr; B P Norman; G Bou-Gharios; J A Gallagher; M Gornall; R Jackson; R Imrich; J Rovensky; M Rudebeck; B Olsson Journal: Mol Genet Metab Rep Date: 2022-02-01