Source: FDA, National Drug Code (US) Revision Year: 2020
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.
Normal individuals and persons heterozygous for cystinosis have WBC cystine concentrations of less than 0.2 and usually below 1 nmol ½ cystine/mg protein, respectively, when measured using the mixed leukocyte assay. Untreated patients with nephropathic cystinosis have elevations of WBC cystine concentration above 2 nmol ½ cystine/mg protein.
After the administration of a single dose of PROCYSBI, peak concentrations of cysteamine were observed at 3 hours post-dose. The nadir of WBC cystine closely followed the peak concentrations at 3.5 hours post-dose, and returned to baseline WBC concentrations at 12 hours-post dose. The cystine concentration in WBC lysate was measured with LC/MS/MS and total protein content in human WBC lysate was measured using the bicinchoninic acid (BCA) assay. A correction factor was applied to the total protein content for the difference in results from the Lowry method. The cystine concentration in nmol ½ cystine/mg protein was calculated by multiplying nmol cystine/mg protein by 2 [see Dosage and Administration (2.5)].
The pharmacokinetics of cysteamine with administration of PROCYSBI were evaluated in 43 patients age ranged from 6 to 26 years (mean age 12 years) with cystinosis and with an estimated glomerular filtration rate of greater than 30 mL/minutes/1.73 m². Table 4 shows the mean pharmacokinetic parameters for PROCYSBI and immediate-release cysteamine bitartrate at steady state. The mean (± SD) dose for PROCYSBI was 656 ± 144 mg/m² (given every 12 hours) and for immediate-release cysteamine bitartrate was 404 ± 88 mg/m² (given every 6 hours).
Table 4. Pharmacokinetic parameters for cysteamine at steady state* after administration of PROCYSBI or immediate-release cysteamine bitartrate:
| Immediate-release cysteamine bitartrate given every 6 hours | PROCYSBI given every 12 hours | |
|---|---|---|
| Cmax (mg/L) | 2.7 ± 1.4 | 3.6 ± 1.8 |
| AUC0-6h (min*mg/L) | 351 ± 153 | NA |
| AUC0-12h (min*mg/L) | NA | 726 ± 339 |
| AUCinf (min*mg/L) | 380 ± 157 | 785 ± 358 |
| Tmax (min) | 73 ± 31 | 188 ± 88 |
| t½ (min) | 90 ± 24 | 253 ± 403 |
| CL/F (L/min) | 1.4 ± 0.8 | 1.2 ± 0.8 |
| Vd/F (L) | 198 ± 159 | 382 ± 404 |
The pharmacokinetics of cysteamine with administration of PROCYSBI are consistent with a delayed-release formulation; the mean Tmax for cysteamine was 188 minutes with PROCYSBI compared with 73 minutes for immediate-release cysteamine bitartrate.
The mean plasma cysteamine peak and AUC were similar when a single PROCYSBI dose of 600 mg was administered with 240 mL orange juice or with 240 mL water. The systemic exposure to cysteamine was similar when PROCYSBI was administered with orange juice as a whole capsule and sprinkled in applesauce in the fasted state. In a food effect study conducted in healthy subjects (n=20), administration of a meal 30 minutes following PROCYSBI administration (intact capsules) decreased Cmax by 34% and AUC0-t by 32% compared to administration of a meal 2 hours post-dose [see Dosage and Administration (2.6)].
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 volume of distribution (Vd/F) was 382 L for PROCYSBI compared with 198 L for immediate-release cysteamine bitartrate.
After each dose of PROCYSBI the cysteamine concentration in the blood continues to decline for approximately 30 minutes and the WBC cystine concentration increases accordingly.
The apparent clearance (Cl/F) of cysteamine was similar between PROCYSBI (1.2 ± 0.8 L/min) and immediate-release cysteamine bitartrate (1.4 ± 0.8 L/min).
The half-life was 253 minutes for PROCYSBI and 90 minutes for immediate-release cysteamine bitartrate.
The pharmacokinetics of cysteamine with administration of PROCYSBI at steady state were evaluated in 11 cysteamine treatment naïve patients between the ages of 1 and 5 years of age with nephropathic cystinosis. A mean (± SD) Cmax of 1.26 ± 0.86 mg/L was reached at an average Tmax of 199 ± 138 minutes and the mean (± SD) dose was 242 ± 93 mg/m². The mean exposure was calculated to be 206 ± 113 minutes*mg/L (AUClast) and 231 ± 123 minutes*mg/L (AUCinf). The mean CLss/F was estimated to be 0.69 ± 0.37 L/minutes with an average half-life (t1/2) of 270 ± 56 minutes. Overall, the pharmacokinetics in patients between the ages of 1 and 5 years of age is comparable with those in older children and adults.
The pharmacokinetics of cysteamine with administration of a single oral dose of 600 mg PROCYSBI were evaluated in non-cystinosis subjects with renal impairment and healthy subjects with normal renal function (eGFR >90 mL/min/1.73m²) matched for age, body mass index and sex.
The mean AUCinf and mean Cmax for cysteamine were 8%, and 3% lower, respectively, in subjects with mild renal impairment (eGFR 60 to 89 mL/min/1.73m²) compared to healthy subjects. In subjects with moderate renal impairment (eGFR 30 to 59 mL/min/1.73m²) and severe renal impairment (≤29 mL/min/1.73m²), the mean AUCinf was 49% and 35% higher and the mean Cmax was 27% and 11% higher, respectively compared to healthy subjects. The mean t½ was 7 hours, 8.3 hours, and 8.8 hours in subjects with mild, moderate, and severe renal impairment, respectively and ranged from 6.6 to 7.5 hours in healthy subjects. The mean CL/F was 1.57, 1.08, and 1.09 L/min in mild, moderate, and severe renal impairment subjects compared to 1.40 to 1.60 L/min in healthy subjects.
In subjects with end-stage renal disease receiving 4 hours of hemodialysis, the geometric mean Cmax and AUCinf of cysteamine was 60% higher when PROCYSBI was administered 3 hours before hemodialysis, and 22% higher when administered 1 hour after completion of hemodialysis compared to healthy subjects. Approximately 4.3% (25.6 mg) of the 600 mg PROCYSBI dose was removed from the body with hemodialysis. The apparent clearance of cysteamine in subjects who received PROCYBI before hemodialysis was approximately 65 mL/min.
The increased exposure to cysteamine in patients with renal impairment compared to healthy subjects is not considered to be clinically meaningful.
An in vitro study indicates cysteamine bitartrate is not an inhibitor of CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). The potential for cysteamine to affect the pharmacokinetics of other drugs via these enzymes is low.
The effect of concomitant omeprazole on the pharmacokinetics of cysteamine was evaluated following co-administration of single PROCYSBI dose of 600 mg with 20 mg of omeprazole in comparison to administration of PROCYSBI alone in healthy subjects in two separate studies. In both studies omeprazole was dosed once daily for 5 days before co-administration with PROCYSBI and single dose PROCYSBI was given either with 240 mL orange juice in one study or with 240 mL water in another study. The pharmacokinetic parameters of cysteamine were not significantly different when PROCYSBI was administered with omeprazole compared to when PROCYSBI was administered alone, regardless whether PROCYSI was administered with orange juice or water [see Dosage and Administration (2.6), Drug Interactions (7.1)].
Cysteamine has not been tested for its carcinogenic potential in long-term animal studies.
PROCYSBI was not mutagenic in the Ames test. It produced a negative response in an in-vitro sister chromatid exchange assay in human lymphocytes, but a positive response in a similar assay in hamster ovarian cells.
Repeat breeding reproduction studies were conducted in male and female rats. Cysteamine was found to have no effect on fertility and reproductive performance at an oral dose of 75 mg/kg per day (450 mg/m² per day, 0.4 times the recommended human dose based on body surface area). At an oral dose of 375 mg/kg per day (2250 mg/m² per day, 1.7 times the recommended human maintenance dose based on body surface area), it reduced the fertility of the adult rats and the survival of their offspring.
Efficacy of immediate-release cysteamine bitartrate was demonstrated in open-label clinical trials of cysteamine hydrochloride and phosphocysteamine.
An open-label clinical trial of cysteamine hydrochloride was conducted in 94 pediatric patients (mainly from the United States) with nephropathic cystinosis. Patients were treated with increasing doses of cysteamine hydrochloride (mean dose 54 mg/kg per day) to attain WBC cystine concentrations of less than 2 nmol ½ cystine/mg protein 5 to 6 hours post-dose. The clinical outcomes were compared with a historical control group of 17 pediatric patients 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 had a mean age of 46 months old at study entry; placebo patients had been diagnosed at about 29 months and had 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 WBC cystine concentration during treatment was 1.7 ± 0.2 nmol ½ cystine/mg protein. There were 70 cysteamine-treated patients with a baseline serum creatinine of less than 2 mg/dL who were followed for at least 1 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 1 patient was followed more than 24 months. Glomerular function among cysteamine-treated 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 pediatric patients, one with poor WBC cystine depletion (defined as median WBC cystine concentrations greater than 3 nmol ½ cystine/mg protein or WBC cystine concentrations not measured at least 2 times per year) and one with good WBC 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 trial. Patients on treatment maintained growth (i.e., did not show increasing growth failure compared with normal scales) although growth velocity did not increase enough to allow patients to catch up to age norms for height.
In another open-label clinical trial, 46 patients who had completed the clinical trial of cysteamine hydrochloride (averaging 6.5 years of treatment) and 93 treatment naïve patients were treated with either cysteamine hydrochloride or phosphocysteamine (patient’s choice). Patients had cystinosis diagnosed by elevated WBC cystine (mean 3.63 nmol ½ cystine/mg). Newly enrolled patients and the 46 continuing patients were required to have serum creatinine less than 3 mg/dL and 4 mg/dL, respectively. Patients were randomized to doses of 1.3 or 1.95 grams/m² per day and stratified according to whether the serum creatinine was above 1.2 mg/dL or not. Doses could be raised if WBC cystine concentrations were approximately 2 nmol ½ cystine/mg protein and lowered due to intolerance. The mean age of the newly enrolled patients was about 49 months for the cysteamine group and about 34 months for the phosphocysteamine group. The mean age of the patients in the long-term follow-up group was about 9 years.
Mean doses were 1.27 grams/m² per day and 1.87 grams/m² per day in the two groups and WBC cystine concentrations averaged 1.72 ± 1.65 nmol ½ cystine/mg protein and 1.86 ± 0.92 nmol ½ cystine/mg protein in the 1.3 grams/m² per day and 1.95 grams/m² per 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. 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.
A clinical trial comparing immediate-release cysteamine bitartrate and PROCYSBI was conducted in 43 (40 pediatric and 3 adult) patients with nephropathic cystinosis (Study RP103-03; NCT01000961). Patient age ranged from 6 to 26 years (mean age 12 years) and 56% were male. Patients with WBC cystine concentrations greater than 2 nmol ½ cystine/mg protein (measured using the mixed leukocyte assay) and estimated glomerular filtration rate (eGFR corrected for body surface area) less than 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 every six hours. PROCYSBI dose adjustments of up to approximately 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 approximately 91% of the average total daily dose of immediate-release cysteamine bitartrate for patients at trial entry.
This trial demonstrated that at steady-state, PROCYSBI administered every 12 hours was non-inferior to immediate-release cysteamine bitartrate administered every 6 hours with respect to the depletion of WBC cystine concentrations (Table 5). 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).
Table 5. Comparison of WBC cystine concentrations in open-label, randomized, cross-over clinical trial participants, 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 concentration in nmol ½ cystine/mg protein (LS Mean ± SE) | 0.44 ± 0.06 | 0.52 ± 0.06 |
| Difference in Treatment effect (LS mean ± SE) [95.8% CI; p-value] | 0.08 ± 0.03 [0.01 to 0.15; <0.0001] | |
Forty of the 41 patients completing the randomized trial continued treatment with PROCYSBI in an open-label extension trial, for a total treatment duration ranging from 1 month to 6.7 years in the study (Study RP103-03-04; NCT01197378). Thirty-six of the 40 patients continued treatment with PROCYSBI for at least 24 months and 20 patients continued treatment for longer than 60 months in the extension trial, and maintained their mean WBC cystine concentrations below 1 nmol ½ cystine/mg protein (measured using the mixed leukocyte assay) over this time period.
Thirteen pediatric patients, aged 2 to 6 years, were also enrolled in the extension trial and treated with PROCYSBI. All of them were on treatment with immediate-release cysteamine bitartrate at the time of enrollment. All 13 patients received at least 18 months of treatment with PROCYSBI, and their mean ± SD WBC cystine concentration (measured using the mixed leukocyte assay) decreased from 1.41 ± 1.03 nmol ½ cystine/mg protein at baseline to 1.22 ± 1.40 nmol ½ cystine/mg protein after 18 months of treatment. Seven of these pediatric patients were able to achieve a WBC cystine concentration (measured using the mixed leukocyte assay) of less than 1.0 nmol ½ cystine/mg protein after 18 months of treatment; their mean ± SD dose of PROCYSBI increased from 0.81 ± 0.25 grams/m² per day at baseline to 0.90 ± 0.25 grams/m² per day after 18 months of treatment.
During extended treatment with PROCYSBI, mean estimates of renal function, as measured by the eGFR, were maintained.
A clinical trial of PROCYSBI (Study RP103-08; NCT01744782) was conducted in 17 patients with a documented diagnosis of nephropathic cystinosis who were naïve to cysteamine treatment (15 patients between the ages of 1 and 5 years, one 9-year old and one 22-year old). The PROCYSBI starting dose was ¼ the maintenance dose of 1 gram/m²/day (actual dosing was based on weight bands using the available capsule strengths, as shown in (Table 1) and the dosage was gradually increased by 10% every 2 weeks. Dosage adjustment was allowed throughout the trial and was based on subject-specific factors (e.g., weight, tolerability) and WBC cystine concentrations. WBC cystine concentrations were obtained 30 minutes after the morning dose collected bi-monthly until the patient’s WBC cystine concentration (using the mixed leukocyte assay) was <1 nmol ½ cystine/mg protein. Treatment duration was at least 12 months.
Fourteen of the 15 patients between 1 year and less than 6 years of age completed 12 months of treatment, and 10 patients completed 18 months of treatment. Thirteen of the 14 patients achieved their highest total daily dosage of PROCYSBI following the 9-month visit (9-month visit for 8 subjects, 12-month visit for 4 subjects, and 18-month visit for 1 subject).
Some patients did not have WBC cystine samples collected at each visit or results were not reportable due to laboratory errors. Thus, the numbers of patients with available WBC cystine data varied across the time points analyzed. In patients with missing samples, dose escalation was continued if the patient’s last reported WBC cystine concentration was >1 nmol ½ cystine/mg protein.
In patients 1 year to less than 6 years, the mean (±SD) WBC cystine concentration on Day 1, 30 minutes following the first dose, was 3.17±2.95 nmol ½ cystine/mg protein (n=15 patients). At 12 months (13 patients with samples), the mean WBC cystine concentration was 0.80 ± 0.60 nmol ½ cystine/mg protein at 30 minutes post dose. At 18 months (9 patients with samples) the mean WBC cystine concentration was 0.74 ± 0.64 nmol ½ cystine/mg protein at 30 minutes post dose.
In patients 1 year to less than 6 years, the mean (±SD) weight percentiles at Day 1 (n=14), 12 months (n=13) and 18 months (n=10) were 3.5 ± 11.1, 11.9 ± 18.3, and 30.1 ± 28.2, respectively, and patient weight z-scores were -4.0 ± 2.1, -2.2 ± 1.7, and -1.3 ± 2.0, respectively. In the same patients, similar trends were observed for height.
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