An Open-Label Investigation of the Pharmacokinetics and Tolerability of Oral Cysteamine in Adults with Cystic Fibrosis

Abstract

Background and ObjectiveCysteamine is licensed for use in nephropathic cystinosis but preclinical data suggest a role in managing cystic fibrosis (CF). This study aimed to determine whether oral cysteamine is absorbed in adult CF patients and enters the bronchial secretions. Tolerability outcomes were also explored.MethodsPatients ≥18 years of age, weighing >50 kg with stable CF lung disease were commenced on oral cysteamine bitartrate (Cystagon®) 450 mg once daily, increased weekly to 450 mg four times daily. Serial plasma cysteamine concentrations were measured for 24 h after the first dose. Participants were reviewed every week for 6 weeks, except at 4 weeks. Plasma cysteamine concentrations were measured 8 h after dosing when reviewed at 1, 2 and 3 weeks and 6 h after dosing when reviewed at 5 weeks. Sputum cysteamine concentration was also quantified at the 5-week assessment.ResultsSeven of the ten participants reported adverse reactions typical of cysteamine, two participants discontinued intervention. Following the first 450-mg dose, mean (SD) maximum concentration (Cmax) was 2.86 (1.96) mg/l, the time corresponding to Cmax (Tmax) was 1.2 (0.7) h, the half-life (t½) was 3.7 (1.7) h, clearance (CL/F) 89.9 (30.5) L/h and volume of distribution (Vd/F) 427 (129) L. Cysteamine appeared to accumulate in sputum with a median (interquartile range) sputum:plasma cysteamine concentration ratio of 4.2 (0.98–8.84).ConclusionOral cysteamine is absorbed and enters the bronchial secretions in patients with CF. Although adverse reactions were common, the majority of patients continued with cysteamine. Further trials are required to establish the risk benefit ratio of cysteamine therapy in CF.

N -Acetyl- l -Cysteine and Cysteamine as New Strategies against Mixed Biofilms of Nonencapsulated Streptococcus pneumoniae and Nontypeable Haemophilus influenzae

“…Cys is also an antioxidant and is licensed for use in nephropathic cystinosis (43). It has also been proposed as suitable for use in Huntington's and Parkinson's diseases, malaria, neuropsychiatric disorders (44), and CF (45)(46)(47). Cys also prevents the formation of, and disrupts already established, Pseudomonas aeruginosa and Enterococcus faecalis biofilms (45,48).…”

Activity of Cysteamine against the Cystic Fibrosis Pathogen Burkholderia cepacia Complex

“…Cysteamine is in late-stage clinical trials for the treatment of cystic fibrosis and is being developed in oral and inhaled forms for acute exacerbations and chronic longer-term maintenance ( 10 – 12 ). An oral form of cysteamine was investigated in an open-label clinical study ( 28 ) in the United Kingdom in which tolerability, absorption, pK, and early evidence of efficacy were assessed in adult CF patients with stable disease. A global two-part registration study for oral cysteamine in acute exacerbations is now being initiated (EudraCT no.…”

Rapid therapeutic advances in CFTR modulator science

“…There continues to be a great deal of effort directed towards new drug development that targets symptomatic aspects of CF, with numerous drugs in the therapeutic pipeline . These include strategies to normalize epithelial sodium transport (eg, inhibitors of the epithelial sodium channel), agents which reduce or help to resolve inflammation, muco‐active compounds, novel anti‐infective therapies, and treatments that address nutritional and GI aspects of CF disease . In addition to these more traditional targets, clinical trials testing highly novel strategies are underway, such as allogenic human mesenchymal stem cells (NCT02866721), iron chelators to disrupt microbial biofilms (NCT02354859), and inhaled nitric oxide that target difficult to treat CF infections (NCT02498535, NCT01958944).…”

“…sodium transport (eg, inhibitors of the epithelial sodium channel), agents which reduce or help to resolve inflammation, muco-active compounds, novel anti-infective therapies, and treatments that address nutritional and GI aspects of CF disease. [12][13][14][15][16][17][18][19] In addition to these more traditional targets, clinical trials testing highly novel strategies are underway, such as allogenic human mesenchymal stem cells (NCT02866721), iron chelators to disrupt microbial biofilms (NCT02354859), and inhaled nitric oxide that target difficult to treat CF infections (NCT02498535, NCT01958944). These approaches focus on important disease pathologies downstream of the genetic defect causing CF and can be applied to CF patients independent of their background genotype.…”