Pharmacokinetics and Distribution of Dapsone (DDS) in Leucocytes After Single-dose and Multiple-dose Administration in Healthy Subjects Genotyped for CYP2C9 and NAT2 and in Patients With Autoimmune Bullous Dermatoses
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 23
- 试验地点
- 1
- 主要终点
- Area under the curve (AUC) for dapsone (DDS) and MA-DDS
研究概览
简要总结
The objectives of the study are
- to evaluate pharmacokinetics, distribution in blood leucocytes, metabolism and methemoglobinemia after single-dose and repeated-dose administration of 100 mg of dapsone in healthy subjects genotyped for CYP2C9 and NAT2
- to evaluate serum through levels, distribution in blood leucocytes and methemoglobinemia after repeated-dose treatment with dapsone in patients with autoimmune bullous dermatoses before and after concomitant treatment with glucocorticoids
详细描述
Dapsone (diamino diphenyl sulphone, DDS) was synthesized by Emil Fromm and Jakob Wittmann in Freiburg (Germany) in 1908. In 1937, the anti-inflammatory potency of dapsone was discovered in experimentally-induced infections in mice. Since 1941, dapsone (as Promin®) is used with great success in the therapy of leprosy. Dapsone is a mainstay in the treatment of leprosy, being one of the components of the multidrug regimen advised by the World Health Organization (WHO).
In 1950, Esteves and Brandão confirmed the efficacy of the drug in patients with dermatitis herpetiformis Duhring. Sneddon and Wilkinson in England reported a remission as caused by dapsone in a patient with subcorneal pustulosis. The efficacy of dapsone in treatment of pemphigus vulgaris was initially reported by Winkelmann and Roth in 1960.
After oral administration, dapsone is almost completely absorbed from the gastrointestinal tract with bioavailability of more than 86 %. Maximum serum concentrations between 0,63 and 4,82 mg/l are attained within 2-8 hours after single doses between 50 mg and 300 mg. At steady-state, the serum concentration fluctuate between 3,26 mg/l and 1,95 mg/l chronic treatment with 100 mg dapsone once daily (s.i.d.).
Dapsone is distributed to all organs, it crosses the blood-brain barrier and placenta and is detected in breast milk.
About 20% of dapsone is excreted unchanged into the urine, 70-85% as water-soluble metabolites additionally to a small amount in feces.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •18 - 45 years
- •preferably males (females will be included if there are not enough males which fulfill the inclusion criteria)
- •Caucasian
- •body weight: > 19 kg/m² and < 27 kg/m²
- •good health as evidenced by the results of the clinical examination, ECG, and the laboratory check-up, which are judged by the clinical investigator not to differ in a clinical relevant way from the normal state
- •written informed consent given by volunteer after being provided with detailed information about the nature, risks, and scope of the clinical trial as well as the expected desirable and adverse effects of the drug
排除标准
- •results of the medical examination or laboratory screening which are judged by the clinical investigator to differ in a clinically relevant way from the normal state
- •female subjects not willing to apply a highly effective method of birth control, which means contraceptive methods with a low failure rate of less than 1% per year during the entire study as stated in the Note for Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (CPMP/ICH/286/95, modifications). These methods include implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner.
- •subjects with existing cardiac or hematological diseases and/ or pathological findings which might interfere with safety, pharmacodynamic effect and/ or pharmacokinetics of dapsone
- •subjects with existing gastrointestinal diseases and/ or pathological findings which might interfere with safety, pharmacodynamic effect and/ or pharmacokinetics of dapsone
- •subjects with acute or chronic organ diseases which could affect drug absorption, metabolism or excretion of dapsone and its metabolites
- •subjects liable to orthostatic dysregulation, fainting, or blackout
- •subjects with known allergic reactions to the investigational product and its adjuvants
- •deficiency of glucose-6-phosphate dehydrogenase (G6PD)
- •subjects positive of HBsAG, HIV and /or drugs
- •subjects with history of psychiatric disorders (depressions, other psychotic disorders)
- •subjects with history of epilepsy
- •gravidity
- •breast feeding mothers, lactation
- •alcohol consumption more than 20 g/day
- •special or uniform nutritional habits, e.g. vegetarians or undercaloric diet
- •intake of grapefruit containing food or beverages and poppy seeds containing products (will not be allowed) 14 days prior to the first drug administration (and) until the last blood sampling of the study
- •subjects with uncommon physical exercise (competitive athletes), excessive physical activity one week before the trial
- •excessive smoking (more than 10 cigarettes or equivalents per day)
- •less than 14 days after last acute disease
- •less than 14 days after last systemic or local drug administration or less than 10 half-lives of the respective drugs
- •blood donation within the last 3 months
- •blocking time due to another clinical trial with investigational products
- •subjects suspected or known not to follow instructions
- •subjects who are unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to as a result of their participation in the study
研究组 & 干预措施
Treatment B
multiple-dose administration of 100 mg dapsone s.i.d. for 7 days; sampling of blood, urine and feces; sampling for leucocytes collection and sampling for additional safety analyses (Met-Hb)
干预措施: Dapsone multiple dose (Drug)
Treatment A
single-dose administration of 100 mg dapsone; sampling of blood, urine and feces; sampling for leucocytes collection and sampling for additional safety analyses (Met-Hb)
干预措施: Dapsone single dose (Drug)
Treatment A
single-dose administration of 100 mg dapsone; sampling of blood, urine and feces; sampling for leucocytes collection and sampling for additional safety analyses (Met-Hb)
干预措施: leucocytes (Biological)
Treatment A
single-dose administration of 100 mg dapsone; sampling of blood, urine and feces; sampling for leucocytes collection and sampling for additional safety analyses (Met-Hb)
干预措施: Met-Hb (Biological)
Treatment B
multiple-dose administration of 100 mg dapsone s.i.d. for 7 days; sampling of blood, urine and feces; sampling for leucocytes collection and sampling for additional safety analyses (Met-Hb)
干预措施: leucocytes (Biological)
Treatment B
multiple-dose administration of 100 mg dapsone s.i.d. for 7 days; sampling of blood, urine and feces; sampling for leucocytes collection and sampling for additional safety analyses (Met-Hb)
干预措施: Met-Hb (Biological)
结局指标
主要结局
Area under the curve (AUC) for dapsone (DDS) and MA-DDS
时间窗: before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 96 hours after single-dose administration and before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24 hours after last repeated-dose administration
AUC0-∞ for single dose administration and AUC0-24h for multiple dose
次要结局
- metabolic clearance (CLM) for dapsone (DDS)(before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96 and 120 hours after single-dose administration and before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96 and 120 hours after last repeated-dose administration)
- rate of adverse events(participants will be followed for the duration of hospital stay (3 weeks) and up to 2 weeks after last study medication, an expected average of 5 weeks)
- erythrocytes(study day 12)
- hemoglobin(study day 12)
- maximal serum concentration (Cmax) for dapsone (DDS) and MA-DDS(before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 96 hours after single-dose administration and before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24 hours after last repeated-dose administration)
- minimal serum concentration (Cmin) for dapsone (DDS) and MA-DDS(before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24 hours after last repeated-dose administration on study-day 15)
- terminal half live (T1/2) for dapsone (DDS) and MA-DDS(before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 96 hours after single-dose administration and before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 96 hours after last repeated-dose administration)
- leucocytes(study day 12)
- hematocrit(study day 12)
- platelets(study day 12)
- timepoint of maximal serum concentration (Tmax) for dapsone (DDS) and MA-DDS(before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 96 hours after single -dose administration and before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24 hours after last repeated-dose administration)
- renal clearance (CLR) for dapsone (DDS) and MA-DDS(before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96 and 120 hours after single-dose administration and before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96 and 120 hours after last repeated-dose administration)
- peak trough fluctuation (PTF) for dapsone (DDS) and MA-DDS(before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24 hours after last repeated-dose administration on study-day 15)
- Met-Hb(before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96 on study day 1 and 14 and additional once on study day 10 and 12)