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

Graham Devereux, Sandra Steele, Kairen Griffiths, Edward Devlin, Douglas Fraser-Pitt, Seonaidh Cotton, John Norrie, Henry Chrystyn, Deborah O'Neil

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Abstract

Background and Objective Cysteamine 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.Methods Patients ≥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.Results Seven of the ten participants reported adverse reactions typical of cysteamine, two participants discontinued intervention. Following the first 450-mg dose, mean (SD) maximum concentration (C max) was 2.86 (1.96) mg/l, the time corresponding to C max (T max) was 1.2 (0.7) h, the half-life (t ½) was 3.7 (1.7) h, clearance (CL/F) 89.9 (30.5) L/h and volume of distribution (V d/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).Conclusion Oral 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.
Original languageEnglish
Pages (from-to)605-612
Number of pages8
JournalClinical Drug Investigation
Volume36
Issue number8
Early online date6 May 2016
DOIs
Publication statusPublished - Aug 2016

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Cysteamine
Cystic Fibrosis
Pharmacokinetics
Sputum
Cystinosis
Lung Diseases
Half-Life

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An Open-Label Investigation of the Pharmacokinetics and Tolerability of Oral Cysteamine in Adults with Cystic Fibrosis. / Devereux, Graham; Steele, Sandra; Griffiths, Kairen; Devlin, Edward; Fraser-Pitt, Douglas; Cotton, Seonaidh; Norrie, John; Chrystyn, Henry; O'Neil, Deborah.

In: Clinical Drug Investigation, Vol. 36, No. 8, 08.2016, p. 605-612.

Research output: Contribution to journalArticle

Devereux, Graham ; Steele, Sandra ; Griffiths, Kairen ; Devlin, Edward ; Fraser-Pitt, Douglas ; Cotton, Seonaidh ; Norrie, John ; Chrystyn, Henry ; O'Neil, Deborah. / An Open-Label Investigation of the Pharmacokinetics and Tolerability of Oral Cysteamine in Adults with Cystic Fibrosis. In: Clinical Drug Investigation. 2016 ; Vol. 36, No. 8. pp. 605-612.
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title = "An Open-Label Investigation of the Pharmacokinetics and Tolerability of Oral Cysteamine in Adults with Cystic Fibrosis",
abstract = "Background and Objective Cysteamine 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.Methods Patients ≥18 years of age, weighing >50 kg with stable CF lung disease were commenced on oral cysteamine bitartrate (Cystagon{\circledR}) 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.Results Seven of the ten participants reported adverse reactions typical of cysteamine, two participants discontinued intervention. Following the first 450-mg dose, mean (SD) maximum concentration (C max) was 2.86 (1.96) mg/l, the time corresponding to C max (T max) was 1.2 (0.7) h, the half-life (t ½) was 3.7 (1.7) h, clearance (CL/F) 89.9 (30.5) L/h and volume of distribution (V d/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).Conclusion Oral 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.",
author = "Graham Devereux and Sandra Steele and Kairen Griffiths and Edward Devlin and Douglas Fraser-Pitt and Seonaidh Cotton and John Norrie and Henry Chrystyn and Deborah O'Neil",
note = "Acknowledgments Trial Steering Committee: Dr Steve Cunningham (chair), Dr Stephen Bourke, Dr Gordon MacGregor. We are grateful to all the participants who took part in the study. We are also grateful to the support from the Clinical Trials Pharmacy at Aberdeen Royal Infirmary. Role of the funding source This study was funded by Health Sciences Scotland (West Medical Building, University Avenue, Glasgow G12 8QQ. UK) and the Cystic Fibrosis Trust (One Aldgate, London. EC3N 1RE. UK). The funders did not contribute to study design, data collection, analysis, this report or the decision to publish.",
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T1 - An Open-Label Investigation of the Pharmacokinetics and Tolerability of Oral Cysteamine in Adults with Cystic Fibrosis

AU - Devereux, Graham

AU - Steele, Sandra

AU - Griffiths, Kairen

AU - Devlin, Edward

AU - Fraser-Pitt, Douglas

AU - Cotton, Seonaidh

AU - Norrie, John

AU - Chrystyn, Henry

AU - O'Neil, Deborah

N1 - Acknowledgments Trial Steering Committee: Dr Steve Cunningham (chair), Dr Stephen Bourke, Dr Gordon MacGregor. We are grateful to all the participants who took part in the study. We are also grateful to the support from the Clinical Trials Pharmacy at Aberdeen Royal Infirmary. Role of the funding source This study was funded by Health Sciences Scotland (West Medical Building, University Avenue, Glasgow G12 8QQ. UK) and the Cystic Fibrosis Trust (One Aldgate, London. EC3N 1RE. UK). The funders did not contribute to study design, data collection, analysis, this report or the decision to publish.

PY - 2016/8

Y1 - 2016/8

N2 - Background and Objective Cysteamine 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.Methods Patients ≥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.Results Seven of the ten participants reported adverse reactions typical of cysteamine, two participants discontinued intervention. Following the first 450-mg dose, mean (SD) maximum concentration (C max) was 2.86 (1.96) mg/l, the time corresponding to C max (T max) was 1.2 (0.7) h, the half-life (t ½) was 3.7 (1.7) h, clearance (CL/F) 89.9 (30.5) L/h and volume of distribution (V d/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).Conclusion Oral 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.

AB - Background and Objective Cysteamine 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.Methods Patients ≥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.Results Seven of the ten participants reported adverse reactions typical of cysteamine, two participants discontinued intervention. Following the first 450-mg dose, mean (SD) maximum concentration (C max) was 2.86 (1.96) mg/l, the time corresponding to C max (T max) was 1.2 (0.7) h, the half-life (t ½) was 3.7 (1.7) h, clearance (CL/F) 89.9 (30.5) L/h and volume of distribution (V d/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).Conclusion Oral 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.

U2 - 10.1007/s40261-016-0405-z

DO - 10.1007/s40261-016-0405-z

M3 - Article

VL - 36

SP - 605

EP - 612

JO - Clinical Drug Investigation

JF - Clinical Drug Investigation

SN - 1173-2563

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