| Reference | [1]. Nitisinone.<br />
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–. 2016 Oct 5.<br />
Nitisinone is an inhibitor of the tyrosine catabolism that is used to treat hereditary tyrosinemia, type 1, in which accumulation of intermediates of tyrosine metabolism causes severe and progressive hepatic and renal injury. Nitisinone has been associated with mild, transient serum aminotransferase elevations, but has not been linked to instances of clinically apparent acute liver injury or jaundice.<br />
PMID: 31643958<br />
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[2]. J Inherit Metab Dis. 2020 Sep;43(5):1014-1023. doi: 10.1002/jimd.12229. Epub 2020 Mar 5.<br />
Nitisinone causes acquired tyrosinosis in alkaptonuria.<br />
Khedr M(1)(2), Cooper MS(3), Hughes AT(1)(2), Milan AM(1)(2), Davison AS(1)(2), Norman BP(2), Sutherland H(4), Jarvis JC(4), Fitzgerald R(5), Markinson L(5), Psarelli EE(6), Ghane P(7), Deutz NEP(8), Gallagher JA(2), Ranganath LR(1)(2).<br />
Author information: (1)Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospitals Trust, Liverpool, UK. (2)Department of Musculoskeletal Biology I, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK. (3)Department of Radiopharmacy, Royal Liverpool University Hospitals Trust, Liverpool, UK. (4)School of Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK. (5)NIHR Royal Liverpool and Broadgreen Clinical Research Facility, Liverpool, UK. (6)Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK. (7)Department of Electrical and Computer Engineering, Texas A&M University, College Station, Texas, USA. (8)Department of Health and Kinesiology, Centre for Translational Research in Aging & Longevity, Texas A&M University, College Station, Texas, USA.<br />
For over two decades, nitisinone (NTBC) has been successfully used to manipulate the tyrosine degradation pathway and save the lives of many children with hereditary tyrosinaemia type 1. More recently, NTBC has been used to halt homogentisic acid accumulation in alkaptonuria (AKU) with evidence suggesting its efficacy as a disease modifying agent. NTBC-induced hypertyrosinaemia has been associated with cognitive impairment and potentially sight-threatening keratopathy. In the context of a non-lethal condition (ie, AKU), these serious risks call for an evaluation of the wider impact of NTBC on the tyrosine pathway. We hypothesised that NTBC increases the tyrosine pool size and concentrations in tissues. In AKU mice tyrosine concentrations of tissue homogenates were measured before and after treatment with NTBC. In humans, pulse injection with l-[13 C9 ]tyrosine and l-[d8 ]phenylalanine was used along with compartmental modelling to estimate the size of tyrosine pools before and after treatment with NTBC. We found that NTBC increased tyrosine concentrations in murine tissues by five to nine folds. It also significantly increased the tyrosine pool size in humans (P < .001), suggesting that NTBC increases tyrosine not just in serum but also in tissues (ie, acquired tyrosinosis). This study provides, for the first time, the experimental proof for the magnitude of NTBC-related acquired tyrosinosis which should be overcome to ensure the safe use of NTBC in AKU.<br />
DOI: 10.1002/jimd.12229 PMID: 32083330<br />
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[3]. Lancet Diabetes Endocrinol. 2020 Sep;8(9):732-733. doi: 10.1016/S2213-8587(20)30222-9. Epub 2020 Aug 18.<br />
Suitability of nitisinone for alkaptonuria.<br />
Häberle J(1).<br />
Author information: (1)Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, Zurich 8032, Switzerland. Electronic address: [email protected].<br />
DOI: 10.1016/S2213-8587(20)30222-9 PMID: 32822593 [Indexed for MEDLINE]<br />
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[4]. Pharmacoeconomic Review Report: Nitisinone (Nitisinone Tablets): (Cycle Pharmaceuticals Ltd.): Indication: For the treatment of patients with hereditary tyrosinemia type 1 in combination with dietary restriction of tyrosine and phenylalanine [Internet].<br />
Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Aug. CADTH Common Drug Reviews.<br />
Nitisinone (Nitisinone Tablets) is indicated for the treatment of hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine. Nitisinone Tablets are available in 2 mg, 5 mg, and 10 mg strengths. The submitted price of nitisinone is based on dose: 2 mg ($12.95), 5 mg ($25.06), and 10 mg ($47.40). The recommended initial dose is 1 mg/kg body weight daily divided into two doses, administered orally. Patients whose plasma and urine succinylacetone are still detectable one month after starting treatment should be increased to 1.5 mg/kg/day, with a maximum of 2 mg/kg/day, based on the evaluation of all clinical parameters. If biochemical response is satisfactory, dosage should only be adjusted according to body weight. The CADTH Common Drug Review (CDR) previously reviewed another brand of nitisinone (Orfadin) for the treatment of HT-1; the CADTH Canadian Drug Expert Committee (CDEC) recommended that nitisinone (Orfadin) be reimbursed for the treatment of adult and pediatric patients with an established diagnosis of HT-1 in combination with dietary restriction of tyrosine and phenylalanine if the following conditions are met: the drug is prescribed by a physician with experience in the diagnosis and management of HT-1, and the price is reduced by at least 74%. CDR recently reviewed a third nitisinone product (MDKNitisinone), with a similar recommendation, noting that the cost of MDK-Nitisinone should not exceed the cost of other nitisinone products. The manufacturer submitted a Markov state–transition model comparing Nitisinone Tablets with diet restriction to diet restriction alone for newborn patients newly diagnosed with HT-1.<br />
PMID: 30942987<br />
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[5]. Pharmacoeconomic Review Report: Nitisinone (MDK-Nitisinone): (MendeliKABS Inc.): Indication: for the treatment of HT-1 in combination with dietary restriction of tyrosine and phenylalanine [Internet].<br />
Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Apr. CADTH Common Drug Reviews.<br />
Nitisinone (MDK-Nitisinone) is an inhibitor of the tyrosine catabolic pathway and is indicated for patients with hereditary tyrosinemia type 1 (HT-1), in combination with dietary restriction of tyrosine and phenylalanine. Nitisinone is available as 2 mg, 5 mg, 10 mg, and 20 mg capsules. The submitted price of nitisinone is based on dose: 2 mg ($14.78), 5 mg ($34.18), 10 mg ($64.70) and 20 mg ($128.10). The recommended initial daily dose of nitisinone is 1 mg/kg body weight divided into two doses administered orally. The dosage of nitisinone should be increased to 1.5 mg/kg/day in patients whose plasma and urine succinylacetone are still detectable one month after starting treatment; a maximum of 2 mg/kg/day may be needed based on evaluation of all biochemical parameters. If the biochemical response is satisfactory, dosage should be adjusted only according to body weight gain. The manufacturer submitted a cost-utility analysis (CUA) that compared the costs and quality of life associated with nitisinone plus dietary restriction with dietary restriction alone in infants less than 30 days of age over a six-year time horizon, from a public health care system perspective (Quebec used as proxy). The manufacturer did not apply a discount rate to costs and benefits in the CUA. The manufacturer also presented a supplementary cost-consequence analysis, based on a 2010 master’s thesis (and subsequent publication) evaluating the costs associated with nitisinone for the treatment of HT-1. Nutritional therapeutic products containing amino acid supplements free of tyrosine and phenylalanine are reimbursed in some jurisdictions but not included as comparators.<br />
PMID: 30457776
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