Dapsone

Dapsone is a sulfone active against a wide range of bacteria.

Dapsones mechanism of action is probably similar to that of the sulfonamides which involves inhibition of folic acid synthesis in susceptible organisms. It is usually considered to be bacteriostatic against M leprae although it may also possess weak bactericidal activity. It is also active against Plasmodium and Pneumocystis carinii. As with sulfonamides, antibacterial activity is inhibited by p-aminobenzoic acid.

Oral administration

Dapsone is almost completely absorbed from the GI tract with peak plasma concentrations occurring about 2-8 hours after a dose. Steady-state concentrations are not obtained until after at least 8 days of daily administration; doses of 100mg daily provide trough concentrations of 0.5 micrograms/ml. About 50-80% of dapsone in the circulation is bound to plasma proteins and nearly 100% of its monoacetylated metabolite is bound.

Dapsone undergoes enterohepatic recycling. It is widely distributed; is present in saliva, breast milk and crosses the placenta. The half-life ranges from 10-80 hours.

Dapsone is acetylated to monoacetyldapsone, the major metabolite, and other mono and diacetyl derivatives. Acetylation exhibits genetic polymorphism. Hydroxylation is the other major metabolite pathway resulting in hydroxylamine dapsone which may be responsible for dapsone-associated methaemoglobinaemia and haemolysis.

Dapsone is mainly excreted in the urine, only 20% of a dose as unchanged drug.

Topical application

In a pharmacokinetic study, male and female subjects 16 years of age or older with acne vulgaris (N=19) applied 2 grams of dapsone gel, 7.5% to the face, upper chest, upper back and shoulders once daily for 28 days. Steady state for dapsone was reached within 7 days of dosing. On Day 28, the mean dapsone maximum plasma concentration (C_max) and area under the concentration-time curve from 0 to 24 hours post dose (AUC_0-24h) were 13.0 ± 6.8 ng/mL and 282 ± 146 ng·h/mL, respectively. The systemic exposure from dapsone gel, 7.5% is expected to be about 1% of that from a 100 mg oral dose.

Long-term safety studies were not conducted with dapsone gel, 7.5%, however, in a long-term clinical study of dapsone gel, 5% treatment (twice daily), periodic blood samples were collected up to 12 months to determine systemic exposure of dapsone and its metabolites in approximately 500 subjects. Based on the measurable dapsone concentrations from 408 subjects (M=192, F=216), obtained at Month 3, neither gender nor race appeared to affect the pharmacokinetics of dapsone. Similarly, dapsone exposures were approximately the same between the age groups of 12-15 years (N=155) and those greater than or equal to 16 years (N=253). There was no evidence of increasing systemic exposure to dapsone over the study year in these subjects.

In an open label safety and pharmacokinetic study in pediatric subjects 9 to 11 years of age with acne vulgaris, a subset of subjects (N=16) received once daily topical application of approximately 2 grams of dapsone gel, 7.5%, to the entire face, shoulders, upper chest and upper back for 8 days. On Day 8, the systemic concentrations were at or near steady state and the mean ± SD systemic concentration of dapsone at 10 hours post dose was 20 ± 12.5 ng/mL.

There are no pre-clinical data.