Pharmacokinetic Studies of Cysteamine Bitartrate Delayed‐Release

Abstract

A twice-daily microsphere formulation of cysteamine bitartrate has been developed for cystinosis and other potential applications. To date, there are no published pharmacokinetic data for cysteamine bitartrate delayed-release in healthy adults. Three randomized open-label, crossover studies to determine the effects of fasting, high fat, and carbohydrate meals on the bioavailability of cysteamine bitartrate delayed-release (600 mg) administered in capsule or sprinkle form to healthy adults. Adverse events were monitored. Fifty-eight adults were studied. Cysteamine absorption (AUC0-24 hours ) was the same for capsule and sprinkle forms during all meal/fasting states. The AUC0-24 hours for capsules while fasted, 30 and 120 minutes before a carbohydrate meal and during a high fat meal were 6,313 ± 329, 4,616 ± 878, 6,691 ± 669, 2,572 ± 295 minutes × µM, respectively, and the mean Cmax values were 29.4 ± 1.7, 20.7 ± 4.9, 31.6 ± 3.0, and 10.9 ± 1.7 µM, respectively. The mean Tmax following fasting and high fat meal were about 3 and 6 hours, respectively. Minor transient GI adverse events occurred. Cysteamine bitartrate delayed-release capsule and sprinkle forms are bioequivalent and optimal absorption occurs during fasting state. High fat diet reduces drug absorption, increases the Tmax and should be avoided at the time of drug ingestion. Cysteamine bitartrate delayed-release (RP103) is best ingested >30 minutes before a carbohydrate-rich meal.

Biopharmaceutical considerations in paediatrics with a view to the evaluation of orally administered drug products – a PEARRL review

“…Drug absorption from innovative paediatric solid formulations, which are usually formulated into a hard capsule, such as multiparticulates and minitablets, show less dependency on the time needed for disintegration, compared to the intact formulation. Differences in the pharmacokinetic profiles have been observed after administration of a capsule and sprinkled formulation in the fed state, achieved by the two formulations in an adult study . McLean et al .…”

The effect of food and liquid pH on the integrity of enteric-coated beads from cysteamine bitartrate delayed-release capsules

“…The bioequivalence between administration of intact cysteamine bitartrate DR capsules and beads from opened capsules mixed with food has been demonstrated. 9 This study did not evaluate the effects of various foods and liquids on halitosis, which is a known transient side effect of cysteamine via its metabolite dimethyl sulfide. A halitosis sub-study of a Phase III clinical trial with DR cysteamine bitartrate associated that formulation with a 26% reduction in exhaled dimethyl sulfide in comparison with immediate-release cysteamine bitartrate.…”

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

“…Studies to date have shown that the PK of both immediate release and DR formulations of cysteamine bitartrate are adversely affected by concomitant food intake. In the case of DR capsules, a high-fat meal substantially reduced exposure (as shown by AUC and C max ) and doubled t max compared with fasting administration [ 10 ]. This has justified the recommendation that cysteamine bitartrate be administered in the fasting state and at least 30 min before a carbohydrate-rich meal [ 4 ].…”

“…A previous pharmacokinetic (PK) study determined that optimal absorption of cysteamine bitartrate DR capsules occurs during the fasting state (> 30 min before a carbohydrate-rich meal) [ 10 ]. It is also recommended that cysteamine bitartrate DR be administered with fruit juice (except grapefruit juice) for maximum absorption [ 4 ].…”