Clinical Trial: Pharmacokinetics and Distribution of Dapsone in Leucocytes After Single-dose and Multiple-dose Administration

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: 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 Bu

Brief Summary:

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

Detailed Summary:

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.

Dapsone is nearly completely metabolized in the liver and in activated polymorphic neutrophils (PMN) and/or mononuclear cells. The major metabolic pathway in the liver is N-acetylation by the polymorphic N-acetyltr
Sponsor: University Medicine Greifswald

Current Primary Outcome: Area under the curve (AUC) for dapsone (DDS) and MA-DDS [ Time Frame: 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


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • maximal serum concentration (Cmax) for dapsone (DDS) and MA-DDS [ Time Frame: 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 [ Time Frame: 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 ]
  • peak trough fluctuation (PTF) for dapsone (DDS) and MA-DDS [ Time Frame: 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 ]
  • timepoint of maximal serum concentration (Tmax) for dapsone (DDS) and MA-DDS [ Time Frame: 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 ]
  • terminal half live (T1/2) for dapsone (DDS) and MA-DDS [ Time Frame: 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 ]
  • renal clearance (CLR) for dapsone (DDS) and MA-DDS [ Time Frame: 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 ]
  • metabolic clearance (CLM) for dapsone (DDS) [ Time Frame: 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 [ Time Frame: 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 ]
  • Met-Hb [ Time Frame: 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 ]
  • leucocytes [ Time Frame: study day 12 ]
  • erythrocytes [ Time Frame: study day 12 ]
  • hemoglobin [ Time Frame: study day 12 ]
  • hematocrit [ Time Frame: study day 12 ]
  • platelets [ Time Frame: study day 12 ]


Original Secondary Outcome: Same as current

Information By: University Medicine Greifswald

Dates:
Date Received: June 30, 2015
Date Started: September 2011
Date Completion:
Last Updated: July 6, 2015
Last Verified: July 2015