Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
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.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

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.