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.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/hÁkg (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 mmol/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.

Nitisinone: a review

“…Nitisinone decreased the urinary excretion of HGA in a concentration-dependent manner, up to serum nitisinone concentrations of about 3 µmol/L. 25 This concentration was reached with a dose of 8 mg daily in seven of eight patients with that dose. These …”

“…13 A long-term LD 50 value lower than the short-term LD 50 was reported to support the hypothesis that the toxicity of nitisinone was linked to its mode of action. 13,[22][23][24][25] Nitisinone and hereditary tyrosinemia type 1…”

“…13,24,25,[101][102][103][104] The drop in HGA concentrations was rapid, with approximately 60% decrease in circulating HGA within 48 hours on 2 mg dose (unpublished data), and thus is an efficacious treatment. 101 Six clinical trials have been undertaken on the use of nitisinone to treat AKU.…”

“…101 Six clinical trials have been undertaken on the use of nitisinone to treat AKU. 24,25,86,[102][103][104] The first study was an early dose ranging study in two older women with AKU. 102 An open-label, single-center study of 9 AKU patients showed that the dose required to decrease HGA significantly was up to 30-fold lower than that used in treating HT1.…”

“…104 Despite the dosage to treat AKU is lower than that to treat HT1, it still causes accumulation of Tyr over the recommended threshold of 400-500 µmol/L with a large interindividual variability, and long-term monitoring of plasma Tyr levels is needed because the metabolic fate of this is largely unknown in AKU. 13,24,25,[102][103][104] It is postulated that treatment with nitisinone should be started as early as possible before renal functions decline and other potentially fatal acute complications develop. 99,100 Nitisinone and neuroblastoma Neuroblastoma, the most common solid neoplasm of childhood outside of the central nervous system, is a neural crest-derived neoplasm.…”