Based on experimental findings that the Cmax and AUC of cysteamine as well as its effect on decreasing cystine levels was greater from the small intestine than from the stomach(19, 20), a delayed-release formula of cysteamine bitartrate (Procysbi→, Horizon Pharma USA and Chiesi Farmaceutici S.p.A., Parma, Italy) was developed. To achieve this, cysteamine is encapsulated in gastric-acid resistant beads. Thus, the drug is released in the small intestine instead of the stomach, as it is the case with immediated release cysteamine.
As described above, our data confirmed the delayed release of DR-cysteamine (Procysbi→), as the maximum effect on cystine was delayed by approximately 90 minutes compared to IR-cysteamine (CystagonⓇ). With DR-cysteamine, the Cmax was reached approximately 120 minutes later than with IR-cysteamine. Additionally, the Tmax for DR-cysteamine was more than two folds higher than for IR-cysteamine, underlining its release in the small intestine. These findings are in line with those of a previous analysis of Langman et al.(14)
Likewise, we could confirm the findings of Belldina et al(21) who saw a lag time (mean lag time 0,44 hours) between the drug concentration of immediate-release cysteamine and its effect: Our data showed that while the Cmax is reached already after 60 minutes, the mean minimum cystine concentration is reached after 90 minutes.
Our data showed no statistically significant difference in the effectiveness of IR-cysteamine and DR-cysteamine in depleting white blood cell cystine levels. Cystine levels were effectively decreased under 0,5 nmol cystine/mg protein under both drugs. There was an average decrease in cystine levels of 58,59% under IR-cysteamine and 51,14 % under DR-cysteamine. In terms of its effect on decreasing mean absolute WBC cystine content, we can confirm previous findings of Langman et al who showed a non-inferiority of DR-cysteamine in comparison to IR-cysteamine.(14) Dohil et al compared a self-manufactured formula of enteric-coated cysteamine with cysteamine and likewise showed that both formulas effectively decrease WBC cystine levels.(22)
It is not only of interest how much cystine levels are decreased, but also how long WBC cystine levels are kept under the target value of 0,5 nmol cystine/mg protein. It has already been proven that immediate release cysteamine is able to keep WBC cystine under the target level of 0,5 nmol/mg protein throughout the whole dosing interval.(21) Our results showed that there was no statistically significant difference in how long the target levels were kept and the point of time when the target value was crossed: Under IR-cysteamine, cystine levels rose above 0,5 nmol cystine/mg protein after a mean time of 250 minutes, indicating a slight underdosing as the next dose is not scheduled until 110 minutes later. Under DR-cysteamine, cystine levels above the target values were also reached already after 250 minutes: As the next dosing interval is scheduled for almost 8 hours later, we suggest that the dosing was probably insufficient, otherwise cystine levels would reach the target value, but would stay there for an insufficient amount of time. The probable underdosing is also suggested by the fact, that at the end of the dosing interval of DR-cysteamine, the mean cystine value had already risen to mean cystine values of 0,74 ± 0,33 nmol cystine/mg protein. With the dose being used in our study, DR-cysteamine would likewise have to be administered more frequently.
Our data do not support the results of Langman et al(14) and Dohil et al(22) who considered 70–80% and 60% respectively of delayed-release cysteamine of the total daily dose of IR-cysteamine dosing as being sufficient. We therefore suggest to initiate therapy with a higher dosing than 70% of the previous cysteamine dosing for the treatment of nephropathic cystinosis, according to the prescribing information (1,30 g/m2 per day, divided into 2 doses). The dosing should then be adjusted according to the results of regular measurements of the cystine levels.
Adherence to cysteamine therapy is challenging, mainly due to the frequent dosing scheme which interrupts patients’ sleep on a daily basis but also because of the numerous side effects, such as nausea and body odor. These side effects have serious implications on patients social life and therefore lead to a diminished compliance, especially in adolescent patients.(11, 12)
In terms of side effects, our study showed a clear advantage for the usage of DR-cysteamine, as the number of patients complaining about nausea and/or body odor or halitosis was much lower, despite the fact that the single dose of DR-cysteamine was higher than a single dose of IR-cysteamine. This effect can be attributed to the release of DR-cysteamine in the small-intestine instead of the stomach, due to its enteric coating, which directly contributes to less gastrointestinal side effects. These findings confirm those of other studies, who also reported ameliorated or even no side effects under delayed-release cysteamine.(23), but are opposed to those of Langman et al who reported more side effects under DR-cysteamine.(14)
The fact that Procysbi→ needs to be administered only twice daily could therefore be yet another reason for an increase in patients’ compliance as the sleep is not interrupted. Our data suggest that a dosing interval of 12 hours would result in an underdosing when giving only 70% of the IR-cysteamine dosing. As previously stated, to achieve satisfactory cystine levels under the target value of 0,5, the dose of DR-cysteamine should probably be increased. This fact is shown by the calculated AUC for IR – and DR cysteamine for 24 hours, which is more than 1,5 fold as high with IR-cysteamine than with DR-cysteamine. Still, more frequent intakes might be necessary as drug release is mainly delayed and not significantly retarded. As seen in Fig. 2, cystine levels increase above the target value of 0,5 before the next dosing is scheduled. This indicates that a 12 hour dosing interval as approved by the manufacturer is insufficient. Our data suggests to increase the intake of ProcysbiⓇ to three times daily, which is already common practice recommended by some pediatricians. Thereby, a more steady decline in cystine levels might be achieved while patients still benefit from a more convenient dosing scheme. Data on how cystine levels are decreased by this dosing regimen need to be studied further.
Strict adherence to therapy with IR-cysteamine significantly delays the onset of complications, such as ESRD, hypothyroidism and diabetes and thus improves patients life expectancy, provided that therapy is started as early as possible.(9) These benefits can only be reached by a diligent patients’ compliance, which we believe can be significantly ameliorated by taking DR-cysteamine, due to its fewer side effects and more comfortable dosing scheme provided that doses are increased.
Nevertheless, as performed in our department, it should be reviewed individually if IR-cysteamine or DR-cysteamine is better tolerated by patients, as there are single cases of patients who report even more side effects under DR-cysteamine.(24)
It is important to investigate the long-term effects of DR-cysteamine. As described above, numerous data about the therapeutic benefits of immediate-release already exist. In the setting of a follow-up, Langman et al have proven optimal cystine levels of 40 patients that had been treated with delayed-release cysteamine for a period of 2 years while additionally the patients’ quality of life was improved.(25) These findings are confirmed by Dohil et al, who did a 6 year follow up of 2 patients treated with the self-manufactured formula of delayed-release cysteamine and likewise concluded satisfactory cystine levels.(26)
Nevertheless, Bäumner et al reported two patients with decreased kidney function under treatment with delayed-release cysteamine for a period of 9 months.(24)
Further studies are needed to obtain more data regarding the long-term effects of delayed-release cysteamine on cystine levels and kidney function.
Regarding the limitations of our evaluation, it must be taken into consideration that the data came from a small number of patients (n = 17) which minimizes statistical significance. However, as nephropathic cystinosis is a rare disease with an estimated number of 150 patients in Germany, it is difficult to obtain data from a higher number of patients. Nevertheless, it is important to analyze these data even when their number is limited, to gain more knowledge regarding this rare disease.
Furthermore, data were obtained after ingestion of a single dose of IR-cysteamine respectively DR-cysteamine. Thus, conclusions drawn from these data are limited, as they do not completely reflect reality, in which a pharmacokinetic steady state of the drugs develops over a certain period of time. These steady-state data still need to be examined in further studies.
Regarding the report of adverse side effects, it must also be taken into consideration, that patients were not blinded, which might have affected their reports.
To conclude, our findings suggest the following recommendations:
Treatment should be initiated with DR-cysteamine in patients with nephropathic cystinosis. The initial dose should be started at a higher dose than suggested by Langman et al(14), while being individually adjusted to the patients’ regularly obtained cystine levels. Additionally, the dosing interval should be increased to 3 times per day. These measures are likely to improve drug efficacy and therapy adherence, thus leading to favorable long term outcomes.
Table 2 shows mean values incl. standard deviations and p-values of pharmacokinetic parameters of 17 patients after ingestion of a single dose of IR-cysteamine (Cystagonâ), DR-cysteamine (Procysbiâ) respectively.
Table 3 demonstrates mean cystine levels (in nmol cystine/mg protein) under a single dose of Cystagonâ and Procysbiâ at different point of times, including standard deviations and p-values.
Table 4 demonstrates mean cysteamine levels in µmol/l under a single dose of IR-cysteamine (Cystagon→) and DR-cysteamine (ProcysbiⓇ) at different point of times, including standard deviations and p-values.
Figure 3 shows the mean C max of plasma cysteamine levels in µmol/l
Figure 4 shows the mean T max (in minutes) under IR-cysteamine and DR-cysteamine