Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract and metabolism products, ATC code: A16A X04.
Mechanism of action
The biochemical defect in hereditary tyrosinemia type 1 (HT-1) is a deficiency of fumarylacetoacetate hydrolase, which is the final enzyme of the tyrosine catabolic pathway.
Orfadin hard capsules is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme which precedes fumarylacetoacetate hydrolase in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, Orfadin hard capsules prevents the accumulation of the toxic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate. Succinylacetone inhibits the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate.

Pharmacodynamics effects
Orfadin hard capsules treatment leads to normalised porphyrin metabolism with normal erythrocyte PBG- synthase activity and urine 5-ALA, 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 normalized during the first week of treatment.
Succinylacetone should not be detectable in urine or plasma when the Orfadin hard capsules dose is properly adjusted.

Clinical efficacy and safety
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 Orfadin hard capsules are summarized in the table below.
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.
Age at onset of symptoms 1 year 2 years
< 2 months                  38%      29%
> 2-6 months                74%      74%
> 6 months                  96%      96%

Treatment with Orfadin hard capsules 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 Orfadin hard capsules 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: NTBC study (N=250)
Number of patients at                Probability of no HCC (95% confidence interval) at start    2 years    4 years      6       2 years         4 years     6 years years
All           250       155        86        15         98%             94%            91% patients                                              (95; 100)       (90; 98)       (81; 100) Start age     193       114        61         8         99%             99%            99% ≤ 24                                                  (98; 100)      (97; 100)       (94; 100) months
Start age     57        41         25         8         92%             82%            75% > 24                                                  (84; 100)       (70; 95)       (56; 95) months

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.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Formal absorption, distribution, metabolism and elimination studies have not been performed with Orfadin hard capsules. In 10 healthy male volunteers, after administration of a single dose of Orfadin hard capsules (1 mg/kg body weight) the terminal half-life (median) of Orfadin hard capsules in plasma was 54 hours. 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 CYP 3A4-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.