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Mechanism of Action

Cysteamine is an aminothiol that participates within lysosomes in a thiol-disulfide interchange reaction converting cystine into cysteine and cysteinecysteamine mixed disulfide, both of which can exit the lysosome in patients with cystinosis.


Normal individuals and persons heterozygous for cystinosis have white blood cell cystine levels of < 0.2 and usually below 1 nmol ½ cystine/mg protein, respectively. Untreated patients with nephropathic cystinosis have elevations of white cell cystine above 2 nmol ½ cystine/mg protein. White blood cell cystine is monitored in these patients to determine adequacy of dosing, levels being measured ½ hour after dosing when treated with PROCYSBI. In a Long-Term Study [see Clinical Studies] entry white blood 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 an immediate-release cysteamine dose range of 1.3 to 1.95 g/m²/day. (See Section on Dose Titration) .


Pharmacokinetic (PK) and pharmacodynamic (PD) relationships following a single dose of PROCYSBI (cysteamine bitartrate) delayed-release capsules was first studied in comparison to a single dose of immediate-release cysteamine bitartrate in a study with nine (9) patients [see Clinical Studies]. Following normalization to a 450 mg dose, the maximum plasma levels Cmax, AUC0-6h and AUC0-12h (calculated directly from the plasma level data for PROCYSBI™ and from doubling the AUC0-6h value for immediate-release cysteamine to represent two doses) were lower for PROCYSBI™ (27.70 ± 14.99 μmol/L, 75.93 ± 39.22 μmol*h/L and 99.26 ± 44.21 μmol*h/L respectively) than for immediate-release cysteamine bitartrate (37.72 ± 12.10 μmol/L, 96.00 ± 37.81 μmol*h/L and 192.00 ± 75.62 μmol*h/L respectively.

The pharmacokinetics of PROCYSBI is consistent with a delayed-release formulation showing a Tmax of 2.78 ± 1.56 h for PROCYSBI 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. After each dose of PROCYSBI the cysteamine concentration in the blood continues to decline for ~ ½ hour and the level of WBC cystine increases accordingly. [see Clinical Studies]

An exploratory study suggested that administering the contents of PROCYSBI (cysteamine bitartrate) delayed-release capsules mixed with a small amount (4 ounces) of applesauce had no effect on the rate and extent of cysteamine absorption as compared to administration of intact capsules. An additional bioequivalence trial (n=20) was conducted in fasted healthy volunteers. In this bioequivalence trial, intact capsules were taken with orange juice instead of applesauce. Analysis showed bioequivalence between whole capsule and sprinkle administration in the fasted state, An exploratory trial shows that food can reduce the systemic exposure of cysteamine, therefore, it is recommended that PROCYSBI be administered at least 30 minutes before or 2 hours after a meal with a high-fat meal.

Clinical Studies

Clinical Trials with Immediate-release Cysteamine

Three open-label clinical trials with either cysteamine hydrochloride or phosphocysteamine were used to support demonstration of efficacy of immediate-release cysteamine bitartrate.

In one of these trials, the National Collaborative Cysteamine Study (NCCS), 94 children (mainly from the United States) with nephropathic cystinosis were treated with increasing doses of cysteamine hydrochloride (mean dose 54 mg/kg/day) to attain white blood cell cystine levels of less than 2 nmol ½ cystine/mg protein 5 to 6 hours post-dose. The trial 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 trial entry. The principal measures of effectiveness were serum creatinine and calculated creatinine clearance and growth (height).

The average median white blood 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. Median follow-up of the placebo group was 20 months; only one patient was followed more than 24 months. Glomerular function among cysteamine patients was maintained over time. Placebo treated patients experienced a gradual rise in serum creatinine. Renal tubular function was not affected by treatment.

Calculated creatinine clearances were evaluated for two groups of children, one with poor white blood cell cystine depletion (defined as median WBC cystine levels > 3 nmol ½ cystine/mg protein or WBC cystine levels not measured at least 2 times per year) and one with good white blood cell cystine depletion. 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.

Height-for-age measurements of treated patients were compared with height-for-age measurements of 143 patients initially screened for inclusion in the NCCS. Patients on treatment maintained growth (i.e., did not show increasing growth failure compared to normal scales) although growth velocity did not increase enough to allow patients to catch up to age norms for height.

The open-label Long Term Trial, initiated in 1988, utilized both cysteamine hydrochloride 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 blood 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 to intolerance. The mean patient age for new patients was about 49 months for for the cysteamine group and about 34 months for the phosphocysteamine group, respectively. The mean patient age for patients in the long-term follow-up group was about 9 years.

Mean doses were 1.27 g/m²/day and 1.87 g/m²/day in the two groups and white blood 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 in the two groups, respectively. In new patients, 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 hydrochloride had similar effects. The long-term follow-up group also had essentially no change in renal function (almost 80% were followed at least 2 years). In four studies of patients with untreated cystinosis, renal death (need for transplant or dialysis) occurred at median age of less than 10 years. [see DOSAGE AND ADMINISTRATION]

Both new patients and patients in the long-term follow-up group maintained height (although they did not catch up from baseline). There was no apparent difference in height maintenance between the two doses.

Clinical Trials with PROCYSBI

Trial 1 (RP103-01) was a single center, single-dose, open-label, non-randomized, 2-period, immediate-release cysteamine bitartrate vs. PROCYSBI pilot study in 9 (8 pediatric and 1 adult) patients with nephropathic cystinosis ages 6 years to 24 years; 78 % were male. The trial reported highly variable inter-patient bioavailability with both immediate-release cysteamine and PROCYSBI. The trial suggested that, when WBC cystine trough levels are used as a measurement of cellular cystine depletion, delayed-release cysteamine (PROCYSBI) administered every 12 hours (Q12H) is as effective as immediate-release cysteamine bitartrate administered every 6 hours (Q6H).

Trials 2, 5 and 6 (RP103-02, RP103-05, and RP103-06 respectively) were PK studies conducted in healthy volunteers. [see Nonclinical Toxicology]

Trial 3 (RP103-03), the pivotal trial for PROCYSBI, was a phase 3 multicenter (US and EU), randomized, crossover, immediate-release cysteamine bitartrate vs. PROCYSBI trial in 43 (40 pediatric and 3 adult) patients with nephropathic cystinosis. Patient age ranged from 6 to 26 years (mean age 12 years) and 56% were male. Patients with white blood cell (WBC) cystine levels > 2 nmol/½ cystine/mg protein and estimated glomerular filtration rate (eGFR corrected for body surface area) < 30 mL/minute/1.73 m² at the time of screening were excluded from the trial. Prior to randomization, patients were to be on a stable dose of immediate-release cysteamine bitartrate administered Q6H. PROCYSBI dose adjustments of up to ~100% of the total daily dose of immediate-release cysteamine bitartrate were allowed by trial criteria. The average total daily dose of PROCYSBI for patients completing the clinical trial was ~91 % of the average total daily dose of immediate-release cysteamine bitartrate for patients at trial entry. [see DOSAGE AND ADMINISTRATION]

Trial 3 demonstrated that at steady-state, PROCYSBI (cysteamine bitartrate) delayed-release capsules administered Q12H was non-inferior to immediate-release cysteamine bitartrate administered Q6H with respect to the depletion of WBC cystine levels (Table 3). Using a linear mixed effects statistical analysis model, the least-square-mean value of WBC cystine was 0.52 ± 0.06 nmol/½ cystine/mg protein after 12 hours under PROCYSBI and 0.44 ± 0.06 nmol/½ cystine/mg protein after 6 hours under immediate-release cysteamine; a difference of 0.08 ± 0.03 nmol/½ cystine/mg protein (95.8 % Confidence Interval = 0.01 to 0.15).

Forty out of forty-one patients completing Trial 3 are continuing treatment with PROCYSBI in an ongoing, open-label extension trial, i.e. Trial 4 (RP10304), for total treatment duration of 24 months. Twenty additional patients (14 pediatric patients, ages 1 to 6 years, and 6 (4 adult and 2 pediatric) renal transplant patients) have also been enrolled in Trial 4. An interim analysis was performed after all enrolled patients from Trial 3 had been treated with PROCYSBI for at least 12 months (n=33) and up to 19 months (n=3). The analysis indicated that patients switched from immediate-release cysteamine to a treatment regimen of PROCYSBI maintained a WBC level < 1 nmol/½ cystine/mg protein for up to 19 months at a total daily dose equal to their total daily dose of immediate–release cysteamine at entry in Trial 3. During extended treatment there has been on average no worsening of the kidney function, as expressed by the estimated glomerular filtration rate (eGFR).

TABLE 3: Comparison of WBC cystine level in Trial 3 patients, who were on a stable dose of immediate-release cysteamine prior to randomization, with WBC cystine less than 2 nmol/½ cystine/mg protein throughout the trial

  Immediate-release cysteamine bitartrate PROCYSBI
WBC cystine level (LS Mean ± SE) in nmol A cystine/mg protein 0.44 ± 0.06 0.52 ± 0.06
Treatment effect (LS mean ± SE; 95.8% CI; p-value) 0.08 ± 0.03 ; 0.01 to 0.15; < 0.0001

Last reviewed on RxList: 5/13/2013
This monograph has been modified to include the generic and brand name in many instances.

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