Viewing Study NCT02493283



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Last Modification Date: 2024-10-26 @ 11:46 AM
Study NCT ID: NCT02493283
Status: COMPLETED
Last Update Posted: 2015-07-09
First Post: 2015-06-30

Brief Title: Pharmacokinetics and Distribution of Dapsone in Leucocytes After Single-dose and Multiple-dose Administration
Sponsor: University Medicine Greifswald
Organization: University Medicine Greifswald

Study Overview

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 Bullous Dermatoses
Status: COMPLETED
Status Verified Date: 2015-07
Last Known Status: None
Delayed Posting: No
If Stopped, Why?: Not Stopped
Has Expanded Access: False
If Expanded Access, NCT#: N/A
Has Expanded Access, NCT# Status: N/A
Acronym: None
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 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 063 and 482 mgl are attained within 2-8 hours after single doses between 50 mg and 300 mg At steady-state the serum concentration fluctuate between 326 mgl and 195 mgl chronic treatment with 100 mg dapsone once daily sid

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 andor 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 01 to 20 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 erythrocyteplasma ratio 033 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-vitroLit 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

Study Oversight

Has Oversight DMC: None
Is a FDA Regulated Drug?: None
Is a FDA Regulated Device?: None
Is an Unapproved Device?: None
Is a PPSD?: None
Is a US Export?: None
Is an FDA AA801 Violation?: None