22/12/2009

Pharmacokinetics of dapsone gel, 5% for the treatment of acne vulgaris

Thiboutot DM, Willmer J, Sharata H, Halder R, Garrett S. Clin Pharmacokinet. 2007;46(8):697-712
Department of Dermatology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033-0850, USA. dthiboutot@psu.edu
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. STUDY PARTICIPANTS AND 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.

                    PMID: 17655376

An evaluation of dapsone gel 5% in the treatment of acne vulgaris

Pickert A, Raimer S.
 Expert Opin Pharmacother. 2009 Jun;10(9):1515-21
Texas Tech University Health Sciences Center Lubbock, TX, USA.
BACKGROUND: Oral dapsone has been available for over 60 years. Its first clinical use was discovered in 1945, when it was found to be efficacious in inhibiting the progression of leprosy. The combined antibacterial and anti-inflammatory pharmacologic activities of dapsone have made it a widely investigated drug, particularly for use in refractory and unusual dermatologic conditions. However, the possibility of significant hematological side effects, even at low doses, has limited its use. Currently, oral dapsone has FDA approval for the treatment of leprosy and dermatitis herpetiformis. The potential of oral dapsone to treat acne vulgaris is well established, but the risks of serious side effects have made it an undesirable drug for use in the relatively healthy acne population. Recently, a topical formulation of dapsone (Aczone, Allergan, Inc., Irvine, CA, USA) has been approved by the FDA for the treatment of acne vulgaris. OBJECTIVE/METHODS: The aims of this study were to review the published literature on dapsone pharmacology and pharmacokinetics, and to evaluate the gel's efficacy and safety in treating acne vulgaris, and finally to provide personal insight into its future as a topical agent for acne vulgaris. RESULTS/CONCLUSIONS: Clinical studies indicate dapsone gel 5% is effective in treating mild to moderately severe acne. It is well tolerated, with pharmacokinetic evidence indicating topical dosing in comparison to oral administration significantly reduces systemic concentrations of the drug, and therefore risk of serious side effects. Data suggests that dapsone gel 5% has the potential to become an established topical drug for the treatment of acne vulgaris. However, studies comparing the clinical effectiveness of the dapsone gel 5% to other available topical antiacne drugs are needed as are studies accessing its usefulness and safety when combined with other acne pharmaceuticals.
PMID: 19505219