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 (C_max).

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).

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).

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