Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Cycle Pharmaceuticals (Europe) Limited, 70 Sir John Rogersons Quay, Dublin 2, D02 R296, Ireland
Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract and metabolism products
ATC code: A16AX04
Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, the second step in the tyrosine metabolism. By inhibiting the normal catabolism of tyrosine in patients with HT-1 and AKU, nitisinone prevents the accumulation of harmful metabolites downstream of 4-hydroxyphenylpyruvate dioxygenase.
The biochemical defect in HT-1 is a deficiency of fumarylacetoacetate hydrolase, which is the final enzyme of the tyrosine catabolic pathway. Nitisinone prevents the accumulation of the toxic intermediates maleylacetoacetate and fumarylacetoacetate. These intermediates are otherwise converted to the toxic metabolites succinylacetone and succinylacetoacetate. Succinylacetone inhibits the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate.
The biochemical defect in AKU is a deficiency of homogentisate 1,2 dioxygenase, the third enzyme of the tyrosine catabolic pathway. Nitisinone prevents the accumulation of the harmful metabolite homogentisic acid (HGA), which otherwise leads to ochronosis of joints and cartilage and thereby the development of the clinical features of the disease.
In patients with HT-1, nitisinone treatment leads to normalised porphyrin metabolism with normal erythrocyte porphobilinogen synthase activity and urine 5-aminolevulinate, decreased urinary excretion of succinylacetone, increased plasma tyrosine concentration and increased urinary excretion of phenolic acids. Available data from a clinical study indicates that in more than 90% of the patients urine succinylacetone was normalised during the first week of treatment. Succinylacetone should not be detectable in urine or plasma when the nitisinone dose is properly adjusted.
In patients with AKU, nitisinone treatment reduces the accumulation of HGA. Available data from a clinical study shows a 99.7% reduction of urinary HGA, and a 98.8% reduction of serum HGA, following nitisinone treatment compared to untreated control patients after 12 months of treatment.
The clinical study was open-labelled and uncontrolled. The dosing frequency in the study was twice daily. Survival probabilities after 2, 4 and 6 years of treatment with nitisinone are summarised in the table below.
Table 2. Probability of survival after treatment with nitisinone:
| NTBC study (N=250) | |||
|---|---|---|---|
| Age at start of treatment | 2 years | 4 years | 6 years |
| ≤2 months | 93% | 93% | 93% |
| ≤6 months | 93% | 93% | 93% |
| >6 months | 96% | 95% | 95% |
| Overall | 94% | 94% | 94% |
Data from a study used as a historical control (van Spronsen et al., 1994) showed the following survival probability.
Table 3. Probability of survival based on historical control:
| Age at onset of symptoms | 1 year | 2 years |
|---|---|---|
| <2 months | 38% | 29% |
| >2-6 months | 74% | 74% |
| >6 months | 96% | 96% |
Treatment with nitisinone was also found to result in reduced risk for the development of hepatocellular carcinoma compared to historical data on treatment with dietary restriction alone. It was found that the early initiation of treatment resulted in a further reduced risk for the development of hepatocellular carcinoma.
The 2-, 4-, and 6-year probability of no occurrence of HCC during nitisinone treatment for patients aged 24 months or younger at the start of treatment and for those older than 24 months at the start of treatment is shown in the following table:
Table 4. Probability of HCC not developing during nitisinone treatment:
| NTBC study (N=250) | |||||||
|---|---|---|---|---|---|---|---|
| Number of patients at | Probability of no HCC (95% confidence interval) at | ||||||
| Start | 2 years | 4 years | 6 years | 2 years | 4 years | 6 years | |
| All patients | 250 | 155 | 86 | 15 | 98% (95; 100) | 94% (90; 98) | 91% (81; 100) |
| Start age ≤24 months | 193 | 114 | 61 | 8 | 99% (98; 100) | 99% (97; 100) | 99% (94; 100) |
| Start age >24 months | 57 | 41 | 25 | 8 | 92% (84; 100) | 82% (70; 95) | 75% (56; 95) |
In an international survey of patients with HT-1 on treatment with dietary restriction alone, it was found that HCC had been diagnosed in 18% of all patients aged 2 years and above.
A study to evaluate the PK, efficacy and safety of once daily dosing compared to twice daily dosing was performed in 19 patients with HT-1. There were no clinically important differences in AEs or other safety assessments between once and twice daily dosing. No patient had detectable succinylacetone (SA) levels at the end of the once-daily treatment period. The study indicates that once daily administration is safe and efficacious across all ages of patients. Data is, however, limited in patients with body weight <20 kg.
The efficacy and safety of 10 mg once daily nitisinone in the treatment of adult patients with AKU have been demonstrated in a randomized, evaluator-blinded, no-treatment controlled, parallel-group 48-months study in 138 patients (69 treated with nitisinone). The primary endpoint was the effect on urinary HGA levels; a 99.7% reduction following nitisinone treatment compared to untreated control patients was seen after 12 months. Treatment with nitisinone was shown to have a statistically significant positive effect on cAKUSSI, eye pigmentation, ear pigmentation, osteopenia of the hip, and number of spinal regions with pain compared to the untreated control. cAKUSSI is a composite score including eye and ear pigmentation, kidney and prostate stones, aortic stenosis, osteopenia, bone fractures, tendon/ligament/muscle ruptures, kyphosis, scoliosis, joint replacements, and other manifestations of AKU. Thus, the lowered HGA levels in nitisinone-treated patients resulted in a reduction of the ochronotic process and reduced clinical manifestations, supporting a decreased disease progression.
Ocular events, such as keratopathy and eye pain, infections, headache and weight gain were reported with a higher incidence in nitisinone-treated than in untreated patients. Keratopathy led to temporary or permanent treatment discontinuation in 14% of nitisinone-treated patients but was reversible upon withdrawal of nitisinone.
No data is available for patients >70 years.
Formal absorption, distribution, metabolism and elimination studies have not been performed with nitisinone. In 23 healthy volunteers, after administration of a single dose of Nityr tablets (10 mg) the terminal half-life (median) of nitisinone in plasma was 59 hours (ranging from 41 to 74 hours).
A population pharmacokinetic analysis has been conducted on a group of 207 HT-1 patients. The clearance and half-life were determined to be 0.0956 l/kg body weight/day and 52.1 hours respectively.
in vitro studies using human liver microsomes and cDNA-expressed P450 enzymes have shown limited CYP3A4-mediated metabolism.
Based on data from a clinical interaction study with 80 mg nitisinone at steady-state, nitisinone caused a 2.3-fold increase in AUC∞ of the CYP2C9 substrate tolbutamide, which is indicative of a moderate inhibition of CYP2C9. Nitisinone caused an approximate 30% decrease in chlorzoxazone AUC∞, indicative of a weak induction of CYP2E1. Nitisinone does not inhibit CYP2D6 since metoprolol AUC∞ was not affected by the administration of nitisinone. Furosemide AUC∞ was increased 1.7-fold, indicating a weak inhibition of OAT1/OAT3 (see sections 4.4 and 4.5).
Based on in vitro studies, nitisinone is not expected to inhibit CYP1A2, 2C19 or 3A4-mediated metabolism or to induce CYP1A2, 2B6 or 3A4/5. Nitisinone is not expected to inhibit P-gp, BCRP or OCT2-mediated transport. Nitisinone plasma concentration reached in clinical setting is not expected to inhibit OATP1B1, OATP1B3 mediated transport.
Nitisinone has shown embryo-foetal toxicity in the mouse and rabbit at clinically relevant dose levels. In the rabbit, nitisinone induced a dose-related increase in malformations (umbilical hernia and gastroschisis) from a dose level 2.5-fold higher than the maximum recommended human dose (2 mg/kg/day).
A pre- and postnatal development study in the mouse showed statistically significantly reduced pup survival and pup growth during the weaning period at dose levels 125- and 25-fold higher, respectively, than the maximum recommended human dose, with a trend toward a negative effect on pup survival starting from the dose of 5 mg/kg/day. In rats, exposure via milk resulted in reduced mean pup weight and corneal lesions.
No mutagenic but a weak clastogenic activity was observed in in vitro studies. There was no evidence of in vivo genotoxicity (mouse micronucleus assay and mouse liver unscheduled DNA synthesis assay). Nitisinone did not show carcinogenic potential in a 26-week carcinogenicity study in transgenic mice (TgrasH2).
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