Mercaptamine Other names: Cysteamine

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.

Cysteamine reduces corneal cystine crystal accumulation acting as a cystine-depleting agent by converting cystine to cysteine and cysteine-cysteamine mixed disulfides.

Human pharmacokinetic assessment following ocular administration of mercaptamine was not performed.

Similarly to other topically administered ocular products, systemic absorption is likely to occur. However it should be considered that the recommended daily dose of cysteamine applied as eye drops is no more than approximately 0.4% of the highest recommended daily oral dose of cysteamine in any age group.

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.

Systemic exposure following ocular administration is anticipated to be low. When there is concomitant use of ocular and oral treatment with cysteamine the contribution to any systemic risk from ocular administration is considered negligible.

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 mercaptamine.