A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Orfadin Pharmacology, Pharmacokinetics, Studies, Metabolism - Nitisinone
Orfadin Pharmacology, Pharmacokinetics, Studies, Metabolism - Nitisinone
CLINICAL PHARMACOLOGY
Clinical Presentation of Hereditary Tyrosinemia Type 1 (HT-1)
Hereditary tyrosinemia type 1 occurs due to a deficiency in
fumarylacetoacetase (FAH), the final enzyme in the tyrosine catabolic pathway.
This disorder is characterized by progressive liver failure,
increased risk of hepatocellular carcinoma, coagulopathy, painful neurologic
crises, and renal tubular dysfunction resulting in rickets. The clinical phenotype
is variable. Most patients present before 6 months of age with the acute form
of the disease. These children exhibit symptoms of acute liver failure, recurrent
bleeding and have a high risk of mortality within the first year of life. In
the subacute form, children present with symptoms between 6 and 12 months of
age and have a less rapid progression of liver disease. In the chronic form,
symptoms do not appear until after one year of age and these patients have a
more gradual progression to liver failure. Patients with chronic HT-1 are at
increased risk of developing hepatocellular carcinoma and progressive renal
tubular dysfunction resulting in secondary hypophosphatemia and rickets. Patients
with all forms of the disease are at risk of painful porphyria-like neurologic
crises, which occur in 5-20% of patients per year as part of the natural history
of the disorder. Dietary restriction of tyrosine and phenylalanine may improve
liver and kidney function but does not prevent the progression of the disease.
Liver transplant can correct most of the metabolic effects of the disorder except
for the renal tubular dysfunction, which may be due to the local production
of toxic metabolites in the kidney.
Mechanism of Action of Nitisinone
Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate
dioxygenase, an enzyme upstream of FAH in the tyrosine catabolic pathway. By
inhibiting the normal catabolism of tyrosine in patients with HT-1, Nitisinone
prevents the accumulation of the catabolic intermediates maleylacetoacetate
and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates
are converted to the toxic metabolites succinylacetone and succinylacetoacetate,
which are responsible for the observed liver and kidney toxicity. Succinylacetone
can also inhibit the porphyrin synthesis pathway leading to the accumulation
of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic
of HT-1
Since Nitisinone inhibits catabolism of tyrosine, use of this
drug can result in elevated plasma levels of this amino acid. Treatment with
Nitisinone, therefore, requires restriction of the dietary intake of tyrosine
and phenylalanine to prevent the toxicity associated with elevated plasma levels
of tyrosine (see WARNINGS).
Pharmacokinetics and Drug Metabolism
Limited information exists on the metabolism, distribution,
and excretion of Nitisinone in rats. Nitisinone was greater than 90% bioavailable
following oral administration of the labeled compound in rats and was distributed
to different organs, particularly the liver and kidney, where radioactivity
remained for 7 days after administration. Nitisinone was biotransformed in rats
and excreted via the urine.
No pharmacokinetic studies of Nitisinone have been conducted
in children or HT-1 patients.
Absorption
The single-dose pharmacokinetics of Nitisinone have been studied
in ten healthy male volunteers aged 19-39 years (median 32 years). Nitisinone,
1 mg/kg body weight, was administered as a capsule and a liquid. The median
time for maximum plasma concentration was 3 hours for the capsule and 15 minutes
for the liquid. The capsule and liquid formulation were found to be bioequivalent
based on an analysis of area under the plasma concentration- time curve and
maximum plasma concentration (Cmax).
Metabolism
No information on the metabolism of Nitisinone in humans is
available.
Excretion
The mean terminal plasma half-life of Nitisinone in healthy
male volunteers was 54 hours.
The effect of food on the pharmacokinetics of Nitisinone has
not been studied.
Special Populations
Geriatric – No pharmacokinetic studies of Nitisinone have been
performed in geriatric patients. Gender – The effect of gender on the pharmacokinetics
of Nitisinone has not been studied. Race – The effect of race on the pharmacokinetics
of Nitisinone has not been studied.
Renal Insufficiency - The effect of renal insufficiency
on the pharmacokinetics of Nitisinone has not been studied.
Hepatic Dysfunction - The effect of hepatic dysfunction
on the pharmacokinetics of Nitisinone has not been studied.
Drug-Drug Interactions
No drug-drug interaction studies have been conducted with Nitisinone.
CLINICAL STUDIES
An open-label study of the use of Nitisinone in patients with
HT-1 was conducted by 96 investigators at 87 hospitals in 25 countries. The
data presented were obtained over a period covering more than six years and
are derived from 207 patients with a diagnosis of HT-1 verified by the presence
of succinylacetone in the urine or plasma. The median age of patients at enrollment
was 9 months (range birth to 21.7 years, see Table 1).
Table 1. Characteristics of the Study Population
| |
N
|
Treatment time in months (Median)
|
|
Total population
|
207
|
22
|
|
Females
|
93
|
23
|
|
Males
|
114
|
21
|
|
Age at start of Nitisinone therapy
|
|
|
|
0-24 months
|
142
|
20
|
|
> 24 months
|
65
|
28
|
The median duration of treatment was 22 months with a range
of 0.1 months to 78 months. Biochemical Effects of Nitisinone Treatment The
efficacy of Nitisinone as an inhibitor of 4-hydroxy-phenylpyruvate dioxygenase
was inferred by the effects of treatment on the following biochemical parameters:
urine succinylacetone, plasma succinylacetone, and erythrocyte porphobilinogen
synthase (PBG) activity. For all 186 patients for whom data are available, the
excretion of succinylacetone in urine was reduced to a level below the reference
limit, which represents the sensitivity of the analytical procedure. The median
time to normalization was 0.3 months. For most patients for whom data are available
(150/172=87%) the plasma concentration of succinylacetone decreased to a level
below the reference. The median time to normalization was 3.9 months. For all
180 patients for whom data are available, the porphobilinogen synthase activity
of erythrocytes increased to within reference limits. The median time to normalization
was 0.3 months. The differences in these indices compared to the start of Nitisinone
treatment were statistically significant (p<0.001).
Effects on Overall Survival
Available data for historical controls show that patients presenting
with HT-1 under 2 months of age and treated with dietary restrictions alone
had 2 and 4-year survival probabilities of 29% and 29%, respectively. This compares
to 2 and 4-year survival probabilities of 88% and 88%, respectively, for patients
presenting with HT-1 under 2 months of age and treated with dietary restrictions
and Nitisinone in this study. Data for historical controls show that patients
presenting with HT-1 under 6 months of age had 2 and 4-year survival probabilities
of 74% and 60%, respectively. This compares to 2 and 4-year survival probabilities
of 94% and 94%, respectively, for patients presenting with HT-1 under 6 months
of age and treated with dietary restrictions and Nitisinone in this study.
Effects on Incidence of Liver Transplantation or Death due
to Liver Failure
Although the long term prognosis of patients treated with Nitisinone
with regard to hepatic function is not yet known, the results of this clinical
study suggest a marked reduction (>75%) in the risk of early onset liver
failure that characterizes the natural history of HT-1.
Effect on Porphyrin Metabolism
Three cases of porphyric crisis, one of which was fatal, were
observed in three patients during the clinical study and in continued clinical
follow-up (0.3% cases per year). This compares to the incidence of 5-20% cases
per year expected as part of the natural history of the disorder.
Effect on Renal Function
Renal function was investigated specifically in the subgroup
of patients exhibiting signs of renal dysfunction prior to treatment. At the
one-year visit, both urine excretion of amino acids and serum concentration
of phosphate were within the reference range in this subgroup. Urinary alpha-1-microglobulin,
used to estimate tubular function, was increased at the start of the study in
this subgroup but was within the normal reference limits after 1 year of treatment.
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