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 m...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-01-01
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| Series: | JIMD Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jmd2.12261 |
| _version_ | 1818943394847653888 |
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| author | Lakshminarayan R. Ranganath Anna M. Milan Andrew T. Hughes Milad Khedr Brendan P. Norman Mohammed Alsbou Richard Imrich Matthew Gornall Nicolas Sireau James A. Gallagher Richard Jackson |
| author_facet | Lakshminarayan R. Ranganath Anna M. Milan Andrew T. Hughes Milad Khedr Brendan P. Norman Mohammed Alsbou Richard Imrich Matthew Gornall Nicolas Sireau James A. Gallagher Richard Jackson |
| author_sort | Lakshminarayan R. Ranganath |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T07:26:38Z |
| format | Article |
| id | doaj.art-5d36e4859dd84f01a498e92ebccc7fb8 |
| institution | Directory Open Access Journal |
| issn | 2192-8312 |
| language | English |
| last_indexed | 2024-12-20T07:26:38Z |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | JIMD Reports |
| spelling | doaj.art-5d36e4859dd84f01a498e92ebccc7fb82022-12-21T19:48:32ZengWileyJIMD Reports2192-83122022-01-01631809210.1002/jmd2.12261Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria—An approach using statistical modellingLakshminarayan R. Ranganath0Anna M. Milan1Andrew T. Hughes2Milad Khedr3Brendan P. Norman4Mohammed Alsbou5Richard Imrich6Matthew Gornall7Nicolas Sireau8James A. Gallagher9Richard Jackson10Departments of Clinical Biochemistry and Metabolic Medicine Liverpool University Hospitals NHS Foundation Trusts Liverpool UKDepartments of Clinical Biochemistry and Metabolic Medicine Liverpool University Hospitals NHS Foundation Trusts Liverpool UKDepartments of Clinical Biochemistry and Metabolic Medicine Liverpool University Hospitals NHS Foundation Trusts Liverpool UKDepartments of Clinical Biochemistry and Metabolic Medicine Liverpool University Hospitals NHS Foundation Trusts Liverpool UKMusculoskeletal Biology and Ageing University of Liverpool, William Henry Duncan Building Liverpool UKFaculty of Medicine Mutah University Karak JordanNational Institute of Rheumatic Diseases Piešťany SlovakiaLiverpool Cancer Trials Unit University of Liverpool Liverpool UKAKU Society Cambridge UKMusculoskeletal Biology and Ageing University of Liverpool, William Henry Duncan Building Liverpool UKLiverpool Cancer Trials Unit University of Liverpool Liverpool UKAbstract 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.https://doi.org/10.1002/jmd2.12261AKUSSIalkaptonuriadisease progressionhomogentisic acidnitisinonesafety |
| spellingShingle | Lakshminarayan R. Ranganath Anna M. Milan Andrew T. Hughes Milad Khedr Brendan P. Norman Mohammed Alsbou Richard Imrich Matthew Gornall Nicolas Sireau James A. Gallagher Richard Jackson Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria—An approach using statistical modelling JIMD Reports AKUSSI alkaptonuria disease progression homogentisic acid nitisinone safety |
| title | Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria—An approach using statistical modelling |
| title_full | Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria—An approach using statistical modelling |
| title_fullStr | Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria—An approach using statistical modelling |
| title_full_unstemmed | Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria—An approach using statistical modelling |
| title_short | Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria—An approach using statistical modelling |
| title_sort | comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria an approach using statistical modelling |
| topic | AKUSSI alkaptonuria disease progression homogentisic acid nitisinone safety |
| url | https://doi.org/10.1002/jmd2.12261 |
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