A Phase 1 Pharmacokinetic Study of Cysteamine Bitartrate Delayed-Release Capsules Following Oral Administration with Orange Juice, Water, or Omeprazole in Cystinosis

Abstract

IntroductionCystinosis is a rare, metabolic, autosomal recessive, genetic lysosomal storage disorder characterized by an accumulation of cystine in various organs and tissues. Cysteamine bitartrate (CB) is a cystine-depleting aminothiol agent approved in the United States and Europe in immediate-release and delayed-release (DR) formulations for the treatment of nephropathic cystinosis in children and adults. It is recommended that CBDR be administered with fruit juice (except grapefruit juice) for maximum absorption. Omeprazole is a proton pump inhibitor that inhibits gastric acid secretion and, theoretically, may cause the premature release of cysteamine by increasing intragastric pH, thereby affecting the PK of CBDR.MethodsThis open-label, three-period, randomized study in healthy adult subjects was designed primarily to compare the pharmacokinetics of CBDR capsules after a single oral dose administered with orange juice, water, or multiple oral doses of omeprazole with water at steady state. A total of 32 subjects were randomly assigned to receive study agents in one of two treatment sequences.ResultsAll subjects completed the study and baseline characteristics of the overall population and the two treatment sequence populations were similar. Peak mean plasma cysteamine concentrations following co-administration of CBDR capsules with orange juice (1892 ng/mL) were higher compared with co-administration with water (1663 ng/mL) or omeprazole 20 mg and water (1712 ng/mL). Mean time to peak plasma concentration was shorter with omeprazole co-administration (2.5 h) compared with orange juice (3.5 h) or water (3.0 h). Statistical comparisons between treatment groups indicated that exposure as assessed by AUC0–t, AUC0–∞, and Cmax were all within the 80–125% bioequivalence ranges for all comparisons. All treatments were generally well tolerated.ConclusionOverall, the pharmacokinetics of cysteamine bitartrate DR capsules are not significantly impacted by co-administration with orange juice, water only, or omeprazole (with water).FundingHorizon Pharma, Inc.

A New and Rapid LC-MS/MS Method for the Determination of Cysteamine Plasma Levels in Cystinosis Patients

“…This value was slightly higher than the peak concentration reported in a phase I pharmacokinetic study on cysteamine bitartrate conducted in adult patients (Cmax range: 1700.0-2000.0 ng/mL) [35]. However, in study by Armas D. and colleagues, the use of delayed-release capsules of cysteamine bitartrate produced a mean Tmax between 2.50 and 3.50 h [35]. Therefore, the use of a different oral formulation could partially explain the difference observed in our Cmax values.…”

“…Similarly, in our study, the median cysteamine concentration for Cmax (post-dose) was 28.00 µM (IQR: 17.62-36.61), corresponding to 2160.20 ng/mL. This value was slightly higher than the peak concentration reported in a phase I pharmacokinetic study on cysteamine bitartrate conducted in adult patients (Cmax range: 1700.0-2000.0 ng/mL) [35]. However, in study by Armas D. and colleagues, the use of delayed-release capsules of cysteamine bitartrate produced a mean Tmax between 2.50 and 3.50 h [35].…”

Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis

“…New Formulations of Cysteamine Cystagon, an immediate-release formulation of cysteamine and the first available treatment for cystinosis, was approved by the FDA in 1994. Although Cystagon effectively lowers cystine levels, it is associated with significant gastrointestinal symptoms (due to gastrin release and acid hypersecretion, which is alleviated by treatment with concomitant proton pump inhibitors [62]) and unpleasant sulfuric body and breath odor [63]. These side effects together with a strict dosing schedule (every 6 hours) substantially influence patients' adherence to treatment and can contribute to compromised clinical outcomes [63].…”

“…These side effects together with a strict dosing schedule (every 6 hours) substantially influence patients' adherence to treatment and can contribute to compromised clinical outcomes [63]. Procysbi, a delayed-release formulation of cysteamine bitartrate, bypasses the stomach and has sustained absorption in the small intestine, resulting in reduced gastrointestinal side effects [62,64]. In addition, it requires only a twice-daily dosing and thereby significantly improves the patient's quality of life by relieving the burdens of interrupted sleep for nighttime dosing [64,65].…”

Challenges for cysteamine stabilization, quantification, and biological effects improvement

“…Armas et al. [ 84 ] showed that the pharmacokinetics of cys bitartrate delayed-release capsules are not affected by co-administration with orange juice, water only, or omeprazole (with water).…”