Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Recordati Rare Diseases, Tour Hekla, 52, avenue du Général de Gaulle, F-92800 Puteaux, France
Pharmacotherapeutic group: Alimentary tract and metabolism product
ATC code: A16AA04
Normal individuals and heterozygous subjects for cystinosis have white cell cystine levels of <0.2, and usually below 1 nmol hemicystine/mg protein, respectively. Individuals with nephropathic cystinosis have elevations of white cell cystine above 2 nmol hemicystine/mg protein.
Cysteamine reacts with cystine to form the mixed disulfide of cysteamine and cysteine. The mixed disulfide is then exported from the lysosomes by an intact lysine transport system. The decrease in leucocyte cystine levels is correlated to the cysteamine plasma concentration over the six hours following the administration of CYSTAGON.
The leucocyte cystine level reaches its minimum (mean (± sd) value: 1.8 ± 0.8 hours) slightly later than the peak plasma cysteamine concentration (mean (± sd) value: 1.4 ± 0.4 hours) and returns to its baseline level as the plasma cysteamine concentration decreases at 6 hours post-dose.
In one clinical study, baseline white cell cystine levels were 3.73 (range 0.13 to 19.8) nmol hemicystine/mg protein and were maintained close to 1 nmol hemicystine/mg protein with a cysteamine dose range of 1.3 to 1.95 g/m²/day.
An earlier study treated 94 children with nephropathic cystinosis with increasing doses of cysteamine to attain white cell cystine levels of less than 2 nmol hemicystine/mg protein 5 to 6 hours post-dose, and compared their outcome with an historical control group of 17 children treated with placebo. The principal efficacy measurements were serum creatinine and calculated creatinine clearance and growth (height). The mean white cell cystine level attained during treatment was 1.7 + 0.2 nmol hemicystine/mg protein. Among cysteamine patients, glomerular function was maintained over time. Placebo treated patients, in contrast, experienced a gradual rise in serum creatinine. Patients on treatment maintained growth as compared to untreated patients. However, growth velocity did not increase enough to allow patients to catch up the normal for their age. Renal tubular function was not affected by treatment. Two other studies have shown similar results.
In all studies, patient response was better when treatment was started at an early age with good renal function.
Following a single oral dose of cysteamine bitartrate equivalent to 1.05 g of cysteamine free base in healthy volunteers, the mean (± sd) values for the time to peak and peak plasma concentration are 1.4 (± 0.5) hours and 4.0 (± 1.0) μg/ml, respectively. In patients at steady state, these values are 1.4 (± 0.4) hours and 2.6 (± 0.9) μg/ml, respectively, after a dose ranging from 225 to 550 mg. Cysteamine bitartrate (CYSTAGON) is bioequivalent to cysteamine hydrochloride and phosphocysteamine.
The in vitro plasma protein binding of cysteamine, which is mostly to albumin, is independent of plasma drug concentration over the therapeutic range, with a mean (± sd) value of 54.1% (± 1.5). The plasma protein binding in patients at steady state is similar: 53.1% (± 3.6) and 51.1% (± 4.5) at 1.5 and 6 hours post-dose, respectively.
In a pharmacokinetic study performed in 24 healthy volunteers for 24 hours, the mean estimate (± sd) for the terminal half-life of elimination was 4.8 (± 1.8) hours.
The elimination of unchanged cysteamine in the urine has been shown to range between 0.3% and 1.7% of the total daily dose in four patients; the bulk of cysteamine is excreted as sulphate.
Very limited data suggest that cysteamine pharmacokinetic parameters may not be significantly modified in patients with mild to moderate renal insufficiency. No information is available for patients with severe renal insufficiency.
Genotoxicity studies have been performed: although in published studies using cysteamine, induction of chromosome aberrations in cultured eukaryotic cell lines has been reported, specific studies with cysteamine bitartrate did not show any mutagenic effects in the Ames test or any clastogenic effect in the mouse micronucleus test.
Reproduction studies showed embryofoetotoxic effects (resorptions and post-implantation losses) in rats at the 100 mg/kg/day dose level and in rabbits receiving cysteamine 50 mg/kg/day. Teratogenic effects have been described in rats when cysteamine is administered over the period of organogenesis at a dose of 100 mg/kg/day.
This is equivalent to 0.6 g/m²/day in the rat, which is less than half the recommended clinical maintenance dose of cysteamine, i.e. 1.30 g/m²/day. A reduction of fertility was observed in rats at 375 mg/kg/day, a dose at which body weight gain was retarded. At this dose, weight gain and survival of the offspring during lactation was also reduced. High doses of cysteamine impair the ability of lactating mothers to feed their pups. Single doses of the drug inhibit prolactin secretion in animals. Administration of cysteamine in neonate rats induced cataracts.
High doses of cysteamine, either by oral or parenteral routes, produce duodenal ulcers in rats and mice but not in monkeys. Experimental administration of the drug causes depletion of somatostatin in several animal species. The consequence of this for the clinical use of the drug is unknown.
No carcinogenic studies have been conducted with CYSTAGON.
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