Pharmacokinetics and Distribution of Dapsone in Leucocytes After Single-dose and Multiple-dose Administration
Condition: Methemoglobinemia; Linear IgA Bullous Dermatosis
MeSH terms: Methemoglobinemia; Skin Diseases; Skin Diseases, Vesiculobullous; Linear IgA Bullous Dermatosis
Study type: Interventional
Phase: Phase 1

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 description: 
      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-acetyltransferase 2 (NAT2) and N-oxidation by cytochrome
      P-450 (CYP) enzymes. Major metabolites are monoacetyl-dapsone (MADDS) and dapsone
      hydroxylamine (DDS-NOH). Dapsone undergoes enterohepatic circulation.

      MADDS is subjected also to significant deacetylation. A constant equilibrium between
      acetylation and deacetylation is reached within a few hours after the oral administration of
      either dapsone or MADDS. The acetylation ratio shows a large interindividual variation,
      ranging from 0.1 to 2.0. These ratios show a bimodal distribution pattern.

      Acetylation is not the rate-determining step in overall elimination of dapsone. The amount of
      MADDS excreted in urine is very low because it is largely deacetylated to dapsone before
      excretion into the urine. Between slow acetylators (SA) and rapid acetylators (RA), there are
      no differences neither in dapsone serum concentrations nor any pharmacokinetic parameters of
      dapsone. Also, the therapeutic response is the same in both acetylator phenotypes.

      However, excretion of both MADDS and its conjugated derivatives is higher in RA. Therefore,
      dapsone may be used for determination of the NAT2 phenotype even though these metabolites
      represent only a very small fraction of the dose.

      MADDS is highly bound to plasma proteins (> 98%), about 20-25 times more tightly than
      dapsone. Presumably, the small fraction of unbound MADDS and its strong binding to plasma
      proteins are reasons for its low availability in erythrocytes (erythrocyte/plasma ratio =
      0.33). Tight protein binding is also the reason behind low glomerular filtration rate of the
      metabolite; therefore the half-life for MADDS is approximately 20-25 hours, similar like for
      dapsone.

      Microsomal N-hydoxylation is the second major metabolic route of dapsone which seems to be
      associated with hematological side effects of the drug. However, the data on excretion of
      free and conjugated DDS-NOH vary widely in the literature. No reliable information is
      available on excretion of hydroxylated MADDS compounds.

      In terms of efficacy and safety of dapsone, most important is the generation of DDS-NOH, that
      also occurs in inflamed lesions of the skin as mediated by activated PMN. Thus, over the
      years, dapsone became a first-line drug in the treatment of dermatitis herpetiformis Duhring,
      Sneddon-Wilkinson-Syndrome and further bullous autoimmune dermatoses. Most recently was
      found, that formation of DDS-NOH is mainly under control of CYP2C9 in-vitro.(Lit.) Because of
      the known CYP2C9 gene polymorphisms (about 4-6 % are poor metabolizers, PM), efficacy of the
      drug in bullous autoimmune dermatoses may be dependent on the metabolizer status of the
      patients.

      The investigators hypothesize, that subjects which are slow acetylators of NAT2 (SA) but
      extensive metabolizers of CYP2C9 (EM) may form significantly higher levels of the active
      metabolite DDS-NOH than rapid acetylators of NAT2 (RA) being PM of CYP2C9 (PM).
    

Intervention name(s): Dapsone single dose; Dapsone multiple dose; leucocytes; Met-Hb
Intervention type(s): Drug; Drug; Biological; Biological
Intervention description(s): Administration of two tablets Dapson-Fatol 50 mg Tabletten (= 100 mg dapsone) and sampling of blood (before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 96 h after single-dose administration), urine (0-24 h, 24-48 h, 48-72 h, 72-96 h, 96 -120 h) and feces (on treatment days 1-5); Administration of two tablets Dapson-Fatol 50 mg Tabletten (= 100 mg dapsone) s.i.d. for 7 days and sampling of blood (before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 96 h after last repeated-dose administration), urine (last treatment day 0-24 h) and feces (on treatment days 12-15); sampling for leucocytes collection: study days -1, 1, 14 and 15; sampling before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 96 h after single-dose administration, before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 96 h after last repeated-dose administration and sampling for additional safety analyses (Met-Hb): study days 10, 12, 14 and hematology on study day 12
Intervention MeSH terms: Dapsone
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: dapsone; blood leucocytes; pharmacokinetics; metabolism