Pharmacokinetics of enteric-coated cysteamine bitartrate in healthy adults: a pilot study

Abstract

What is already known about this subject: Cysteamine bitartrate is taken lifelong, every 6 h and for the treatment of cystinosis. Recent studies using cysteamine for for other diseases such as neurodegenerative disorders adopt the same dosing regimen for cysteamine. Regular cysteamine bitartrate (Cystagon) may cause upper gastrointestinal symptoms in some patients.

What this study adds: This is the only study that provides pharmacokinetic data for cysteamine delivered in an enteric-release preparation in normal subjects. EC-cysteamine is very well tolerated and does not cause increased gastrin concentrations, even at relatively high doses. EC-cysteamine at the higher dose results in better drug uptake as measured by Cmax and AUC and is more likely to be effective.

Aims: Cysteamine bitartrate (Cystagon) is the approved treatment for cystinosis. Poor compliance and patient outcome may occur because the drug needs to be taken every 6 h and in some patients causes gastrointestinal symptoms due to hypergastrinaemia. A formulation of cysteamine requiring twice daily ingestion would improve the quality of life for these patients. This study compares the pharmacokinetics and gastrin production following cysteamine bitartrate non-enteric-coated and cysteamine bitartrate enteric-coated in normal healthy subjects.

Methods: Enteric-coated cysteamine was prepared. Following single doses of cysteamine bitartrate non-enteric-coated 450 mg and cysteamine bitartrate enteric-coated 450 mg and 900 mg, serial plasma cysteamine and gastrin concentrations were measured. Two subjects also received cysteamine bitartrate non-enteric-coated 900 mg. Gastrointestinal (GI) symptoms were recorded.

Results: Six healthy adults (mean age 20.7 years, range 18-24 years; mean weight 59.3 kg) received drug. All post-dose gastrin concentrations were within the normal range (<100 pg ml(-1)). The tmax following cysteamine bitartrate non-enteric-coated (mean and SD is 75+/-19 min) was shorter than cysteamine bitartrate enteric-coated (220+/-74 min) (P=0.001), but only the Cmax and AUC estimates following 900 mg cysteamine bitartrate enteric-coated were significantly greater than any of the other preparations or doses (P<0.05). One patient had GI symptoms following both 900 mg cysteamine bitartrate non-enteric-coated and cysteamine bitartrate enteric-coated.

Conclusion: Although patient numbers were low, single high doses of cysteamine bitartrate enteric-coated were better tolerated than similar doses of cysteamine bitartrate non-enteric-coated in the healthy subjects and all had normal gastrin concentrations. The delayed tmax following cysteamine bitartrate enteric-coated suggested that the cysteamine was released enterically.

Figures

Figure 1

(A) Plasma cysteamine concentrations in six subjects (1–6) after a single dose of cysteamine bitartrate non-enteric-coated 450 mg (red), cysteamine bitartrate enteric-coated 450 mg (yellow) and cysteamine bitartrate enteric-coated 900 mg (blue) and from two patients (5 and 6) after cysteamine bitartrate non-enteric-coated 900 mg (green). (B) The mean plasma cysteamine concentrations in the six subjects (1–6) after cysteamine bitartrate non-enteric-coated 450 mg (red), cysteamine bitartrate enteric-coated 450 mg (yellow) and cysteamine bitartrate enteric-coated 900 mg (blue). The ‘double-peak’ appearance of the of the mean concentration profiles following 900 mg cysteamine bitartrate enteric-coated represents a wide distribution of tmax values rather than sustained release of the formulation. Error bars are standard deviation. (C) Plasma cysteamine concentrations in two patients (5 with diamonds and 6 with circles) after a single dose of cysteamine bitartrate non-enteric-coated 450 mg (red), cysteamine bitartrate enteric-coated 450 mg (yellow), cysteamine bitartrate non-enteric-coated 900 mg (green) and cysteamine bitartrate enteric-coated 900 mg (blue). Subject 5 vomited 1 h after receiving cysteamine bitartrate non-enteric-coated 900 mg and 3.5h after receiving cysteamine bitartrate enteric-coated 900 mg