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/½ cystine/mg protein,
respectively. Individuals with nephropathic cystinosis have elevations of white
cell cystine above 2 nmol/½ 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/½ cystine/mg protein (range
0.13 to 19.80 nmol/½ cystine/mg protein) and were maintained close to
1 nmol/½ 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/½ 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® (cysteamine bitartrate) 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 Âµg/mL and 6.3 Âµg•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/½ cystine/mg protein and returning to baseline level 6 hours post dose.
The mean white cell cystine concentration and mean cysteamine plasma concentration-time
profile is shown below:
Most clinical data have been developed using cysteamine HCl or phosphocysteamine solutions. In all discussions that follow, administered amounts of various cysteamine salts will be expressed as amounts of cysteamine free base.
There are approximately 200 pre-transplant cystinosis patients in the United
States with nephropathic cystinosis and clinical studies have included almost
all of them, in addition to about 40 studied in the United Kingdom. For all
patients, mean age at entry into studies was just under 4 years. Patients were
approximately equally divided between genders and about 85% were white, 9% were
black, and 3% were hispanic.
The National Collaborative Cysteamine Study (NCCS) treated 94 children (mainly from the United States) with nephropathic cystinosis with increasing doses of cysteamine HCl (mean dose 54 mg/kg/day) to attain white cell cystine levels of less than 2 nmol/½ cystine/mg protein 5 to 6 hours post-dose, and compared their outcome with an historical control group of 17 children who had been in the placebo group of a randomized placebo-controlled trial of ascorbic acid. Cysteamine treated patients had been diagnosed at a mean age of 22 months and were a mean age of 46 months old at study entry; placebo patients had been diagnosed at about 29 months and were a mean age of about 52 months old at study entry. The principal measures of effectiveness were serum creatinine and calculated creatinine clearance and growth (height).
The average median white cell cystine level attained during treatment in the
NCCS was 1.7 ± 0.2 nmol/½ cystine/mg protein. There were 70 cysteamine
patients with baseline serum creatinine less than 2 mg/dL who were followed
for at least a year and 17 placebo patients. Twelve of the 94 cysteamine treated
patients required early dialysis or renal transplant. Median follow-up of cysteamine
patients was over 32 months and 20% were followed more than 5 years. For the
placebo group median follow-up was 20 months and only one was followed more
than 24 months. Among cysteamine patients glomerular function was maintained
over time despite the longer period of treatment and follow-up. Placebo treated
patients, in contrast, experienced a gradual rise in serum creatinine. Height,
corrected for age, was compared for treated patients with the height, at the
various ages patients appeared, of the 143 patients initially screened for inclusion
in the NCCS. Patients on treatment maintained growth (did not show increasing
growth failure compared to normals) although growth velocity did not increase
enough to allow patients to catch up to age norms. Renal tubular function was
not affected by treatment.
Calculated creatinine clearances were evaluated for two groups of children,
one with poor white cell cystine depletion and one with good white cell cystine
depletion as shown in Table I. The final mean creatinine clearance of the good
depletion group was 20.8 ml/min/1.73 m2 greater than the mean for
the poor depletion group, despite the older mean age of the good depletion group.
CREATININE CLEARANCE CHANGES BYWHITE CELL CYSTINE DEPLETION
| Creatinine Clearance
| Poor Depletion1
(n = 18)
| 4.2 ± 1.8
|| 6.5 ± 0.5
|| 33.6 ± 17.0
|| 29.7 ± 5.4
| Good Depletion2
(n = 19)
| 3.3 ± 2.2
|| 7.2 ± 0.7
|| 44.3 ± 15.0
|| 50.5 ± 5.1
| (95% confidence limits on difference between
final creatinine clearances, 6.1 and 35.5 ml/min/1.73m2, despite
older mean age of good depletion group.)
1Median leukocyte cystine levels were over 3 nmol/½
cystine/mg protein or were not measured atleast 2 times per year. Patients
did receive cysteamine for at least 1 year.
2Median leukocyte cystine levels were less than 1 nmol/½
cystine/mg protein and received cysteamine for at least 1 year.
The Long Term Study, initiated in 1988, utilized both cysteamine HCl and phosphocysteamine
(patient's choice) in 46 patients who had completed the NCCS (averaging 6.5
years of treatment) and 93 new patients. Patients had cystinosis diagnosed by
elevated white cell cystine (mean 3.63 nmol/½ cystine/mg). New patients
and 46 continuing patients were required to have serum creatinine less than
3.0 mg/dL and 4.0 mg/dL, respectively. Patients were randomized to doses of
1.3 or 1.95 g/m2/day and stratified according to whether the serum
creatinine was above 1.2 mg/dL or not. Doses could be raised if white cell cystine
levels were approximately 2 nmol/½ cystine/mg protein and lowered due
Mean doses were 1.27 g/m2/day and 1.87 g/m2/day in the
two groups and white cell cystine levels averaged 1.72 ± 1.65 nmol/½
cystine/mg protein and 1.86 ± 0.92 nmol/½ cystine/mg protein in
the 1.3 and 1.95 g/m2/day groups, respectively. In new patients,
a group similar in age to the NCCS group, serum creatinine was essentially unchanged
over the period of follow-up (about half of the patients were followed for 24
months) and phosphocysteamine and cysteamine HCl had similar effects. The long-term
follow-up group, about nine years old on average at entry, stayed in the study
(almost 80% were followed at least 2 years) and had essentially no change in
renal function. In four studies of untreated cystinosis, renal death (need for
transplant or dialysis) occurred at median age of less than 10 years. Both groups
maintained height (although they did not catch up from baseline). There was
no apparent difference between the two doses.