Dataset Information

Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria-An approach using statistical modelling.

ABSTRACT:

Background

Outcomes from studies employing nitisinone 10 mg and 2 mg in alkaptonuria were compared.

Patients and methods

Sixty-nine patients in each of the nitisinone (10 mg daily) and controls of suitability of nitisinone in alkaptonuria 2 (SONIA 2), as well as 37 and 23 in nitisinone (2 mg daily) and control cohorts at the National Alkaptonuria Centre (NAC), respectively, were followed up for 4 years. Severity of alkaptonuria (AKU) was assessed by the AKU Severity Score Index (AKUSSI). 24-h urine homogentisic acid (uHGA₂₄), serum HGA (sHGA), serum tyrosine (sTYR) and serum nitisinone (sNIT) were also analysed at each time point. Dietetic support was used in the NAC, but not in SONIA 2. Safety outcomes were also compared. All statistical analyses were post hoc.

Results

The slope of the AKUSSI was 0.55, 0.19, 0.30, and 0.06 per month in the control NAC, nitisinone NAC, control SONIA 2, and nitisinone SONIA 2 cohorts, respectively. The intersection of the slopes on the x-axis was -132, -411, -295, and - 1460 months, respectively. The control and nitisinone slope comparisons were statistically significant both in the NAC (p < 0.001) and the SONIA 2 (p < 0.001). Corneal keratopathy occurred in 3 and 10 patients in the NAC and SONIA 2, respectively.

Discussion

The nitisinone 10 mg dose decreased disease progression more than the 2 mg dose although the incidence of corneal keratopathy was 14.5% and 4.9%, respectively.

Conclusion

Nitisinone 10 mg decreased urine and serum HGA, increased serum tyrosine, and decreased disease progression more than 2 mg. Low-protein dietetic support may be needed to mitigate tyrosinaemia following nitisinone.

Highlights

Nitisinone 10 mg apparently slows alkaptonuria disease progression more than 2 mg in adults.Corneal keratopathy during nitisinone therapy was more common in men.Serum nitisinone concentrations increased significantly over time.Nitisinone may inhibit cytochrome P450 self catabolism.

SUBMITTER: Ranganath LR

PROVIDER: S-EPMC8743340 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:The homogentisic acid-lowering therapy nitisinone is being evaluated for the treatment of alkaptonuria (AKU) at the National Centre for AKU. Beyond hypertyrosinemia, the wider metabolic consequences of its use are largely unknown. The aim of this work was to evaluate the impact of nitisinone on the serum metabolome of patients with AKU after 12 and 24?months of treatment. Methods:Deproteinized serum from 25 patients with AKU (mean age[±SD] 51.1 ±?14.9?years, 12 male) was analyzed using the 1290 Infinity II liquid chromatography system coupled to a 6550 quadrupole time-of-flight mass spectrometry (Agilent, UK). Raw data were processed using a batch targeted feature extraction algorithm and an accurate mass retention time database containing 469 intermediary metabolites (MW 72-785). Matched entities (±10 ppm theoretical accurate mass and ±0.3?minutes retention time window) were filtered based on their frequency and variability (<25% CV) in group quality control samples, and repeated measures statistical significance analysis with Benjamini-Hochberg false discovery rate adjustment was used to assess changes in metabolite abundance. Results:Eight metabolites increased in abundance (log2 fold change [FC] 2.1-15.2, P <?.05); 7 of 8 entities were related to tyrosine metabolism, and 13 decreased in abundance (log2 FC 1.5-15.5, P <?.05); including entities related to tyrosine (n = 2), tryptophan (n = 3), xanthine (n = 2), and citric acid cycle metabolism (n = 2). Conclusions:Evaluation of the serum metabolome of patients with AKU showed a significant difference in the abundance of several metabolites following treatment with nitisinone, including a number that have not been previously reported; several of these were not related to the tyrosine metabolic pathway. Synopsis:Nitisinone therapy has a significant impact on several metabolites beyond the tyrosine metabolic pathway, several of which appear to be related to the redox state of the cell.