Pharmacokinetics of dapsone gel, 5% for the treatment of acne vulgaris.
BACKGROUND
Oral dapsone has been available for over 60 years and has been used to treat severe acne vulgaris; however, the oral formulation is known to cause dose-dependent haematological reactions and is currently indicated only for diseases such as dermatitis herpetiformis and Hansen's disease. A gel formulation of dapsone was recently developed to treat acne vulgaris. As dapsone is administered topically, it was expected that systemic absorption would be considerably lower than that observed with oral dapsone therapy, thereby avoiding any adverse haematological effects.


OBJECTIVE
To report the pharmacokinetic profile of topically applied dapsone gel, 5% in the treatment of acne vulgaris.


METHODS
Three prospective, open-label studies enrolled a total of 548 subjects with acne vulgaris: two phase I pharmacokinetic studies (crossover and drug interaction) and one phase III long-term safety study. In the crossover study (n = 18), topical dapsone gel applied twice daily for a total of 14 days to 22.5% of the body surface area was compared with a single dose of oral dapsone 100mg (the typical clinical dose). In the drug-interaction study (n = 24), oral trimethoprim/sulfamethoxazole monotherapy, topical dapsone gel monotherapy and the two in combination were used twice daily for 7, 21 and 7 days, respectively. In the long-term safety study (n = 506), topical dapsone gel was applied twice daily to acne-affected areas for up to 12 months. Blood samples were drawn at various timepoints in each study to assess drug and metabolite concentrations. Systemic concentrations of dapsone, N-acetyl dapsone, dapsone hydroxylamine, trimethoprim and sulfamethoxazole were determined, according to the study design.


RESULTS
In the crossover study, the mean area under the plasma concentration-time curve (AUC) from 0 to 24 hours for dapsone was 417.5 ng x h/mL after 2 weeks of dapsone gel therapy (n = 10), compared with an AUC from time zero to infinity of 52,641 ng x h/mL after a single dose of oral dapsone; this represents a 126-fold lower systemic exposure for dapsone gel at typical therapeutic doses. In the drug-interaction study, the AUC from 0 to 12 hours for dapsone was 221.52 ng x h/mL after 3 weeks of dapsone gel monotherapy compared with 320.3 ng x h/mL after 1 week of coadministration with trimethoprim/sulfamethoxazole. In the long-term safety study, the mean plasma dapsone concentrations ranged from 7.5 to 11 ng/mL over 12 months. Overall, total systemic exposures to dapsone and its metabolites were approximately 100-fold less for dapsone gel than for oral dapsone, even in the presence of trimethoprim/sulfamethoxazole. There were no reports of any haematological adverse events.


CONCLUSIONS
Topical application of dapsone gel in various settings ranging from 2 weeks to 12 months resulted in systemic exposures to dapsone and its metabolites that were approximately 100-fold less than those after oral dapsone at a therapeutic dose level. The concentrations of dapsone and its metabolites reached steady state and did not increase during prolonged treatment.
Thiboutot
Diane M
DM
Department of Dermatology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033-0850, USA. dthiboutot@psu.edu
Willmer
Jonathan
J
Sharata
Harry
H
Halder
Rebat
R
Garrett
Steven
S
D000152:Acne Vulgaris / Q000188:drug therapy*; D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents; D019540:Area Under Curve; D002648:Child; D018592:Cross-Over Studies; D003622:Dapsone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005782:Gels; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D010599:Pharmacokinetics
D000890:Anti-Infective Agents; D005782:Gels; D003622:Dapsone