CYSTAGON� (cysteamine bitartrate) Capsules for oral administration, contain cysteamine bitartrate, a cystine depleting agent which lowers the cystine content of cells in patients with cystinosis, an inherited defect of lysosomal transport. CYSTAGON� is the bitartrate salt of cysteamine, an aminothiol, beta-mercaptoethylamine. Cysteamine bitartrate is a highly water soluble white powder with a molecular weight of 227 and the molecular formula C2H7NS � C4H6O6 Mechanism of Action
Cystinosis is an autosomal recessive inborn error of metabolism in which the transport of cystine out of lysosomes is abnormal; in the nephropathic form, accumulation of cystine and formation of crystals damage various organs, especially the kidney, leading to renal tubular Fanconi Syndrome and progressive glomerular failure, with end stage renal failure by the end of the first decade of life. In four studies of cystinosis patients before cysteamine was available, renal death (need for transplant or dialysis) occurred at median age of less than 10 years. Patients with cystinosis also experience growth failure, rickets, and photophobia due to cystine deposits in the cornea. With time most organs are damaged, including the retina, muscles and central nervous system.
Cysteamine is an aminothiol that participates within lysosomes in a thiol-disulfide interchange reaction converting cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome in patients with cystinosis.
Pharmacokinetics and Pharmacodynamics
Normal individuals and persons heterozygous for cystinosis have white cell cystine levels of < 0.2 and usually below 1 nmol/� cystine/mg protein, respectively. Individuals with nephropathic cystinosis have elevations of white cell cystine above 2 nmol/� cystine/mg protein. White cell cystine is monitored in these patients to determine adequacy of dosing, levels being measured 5 to 6 hours after dosing. In the Long-Term Study (see CLINICAL TRIALS, below) entry white cell cystine levels were 3.73 nmol/� cystine/mg protein (range 0.13 to 19.80 nmol/� cystine/mg protein) and were maintained close to 1 nmol/� cystine/mg protein with a cysteamine dose range of 1.3 to 1.95 g/m2/day. After administration of cysteamine HCl, leukocyte cystine levels fall, with minimum levels at approximately 1 hour.
Because cysteamine HCl has an unpleasant taste and odor, other formulations have been developed, including phosphocysteamine, the phosphorothioester of cysteamine that is rapidly converted to cysteamine in the gut, and cysteamine bitartrate (CYSTAGON�). Cysteamine bitartrate has been shown in a transfer study in 8 patients to maintain white cell cystine levels below 1 nmol/� cystine/mg protein when substituted for cysteamine HCl or phosphocysteamine. Total cysteamine levels 2 and 6 hours post-dosing were higher after cysteamine bitartrate than for the solutions.
The pharmacokinetics and pharmacodynamics of CYSTAGON� were studied in eleven pediatric patients with nephropathic cystinosis who received 225 to 550 mg of cysteamine bitartrate every 6 hours daily for more than one year. Following repeated oral administration of 225 to 550 mg cysteamine bitartrate, the mean time to maximum plasma concentration (Tmax) occurred at about 1.4 hours post dose with mean steady-state peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of 2.6 �g/mL and 6.3 �g?hr/mL, respectively. The apparent volume of distribution and apparent plasma clearance of cysteamine were 156 L and 1.2 L/min, respectively.
Cysteamine was moderately bound to human plasma proteins, predominantly to albumin, with mean protein binding of about 52%. Plasma protein binding was independent of concentration over the concentration range achieved clinically with the recommended doses.
The pharmacodynamic response increased with the plasma cysteamine concentration, with maximum response occurring approximately 1.8 hours post dose with an average reduction of white cell cystine concentration of about 0.46 nmol/� cystine/mg protein and returning to baseline level 6 hours post dose. CYSTAGON� is indicated for the management of nephropathic cystinosis in children and adults.
