Safety and Pharmacokinetics of Once-Daily Dapsone Gel, 7.5% in Patients With Moderate Acne Vulgaris

October 2016 | Volume 15 | Issue 10 | Original Article | 1250 | Copyright © 2016

Michael T. Jarratt MD,a Terry M. Jones MD,b Joan-En Chang-Lin PhD,c Warren Tong PharmD MS,c David R. Berk MD,c Vince Lin PhD,c and Alexandre Kaoukhov MDc

aDermResearch, Inc, Austin, TX bDermataloge, Bryan, TX cAllergan plc, Irvine, CA

Abstract

BACKGROUND: Reducing the dosing frequency of topical acne treatments to once daily may improve adherence. OBJECTIVE: Evaluate pharmacokinetics (PK), safety, and tolerability of 3 formulations of once-daily dapsone gel, 7.5% and of twice-daily dapsone gel, 5% over 28 days in patients with moderate acne vulgaris. METHODS: This phase 1, multicenter, parallel-group study randomized males and females aged 16 to 35 years to 1 of 3 dapsone gel, 7.5% formulations (DAP-11078, DAP-11079, or DAP-11080 double-blind; applied once daily) or to dapsone gel, 5% (investigator-blinded only, applied twice-daily). Blood samples were collected for PK assessments of dapsone and its metabolites, N-acetyl dapsone (NAD) and dapsone hydroxylamine (DHA), before the morning dose on days 1, 7, 14, 18, 21, 26, 27, and 28, and at several follow-up time points (days 29–32). Safety profile assessments included adverse events (AEs), physical examinations, laboratory tests, and local tolerability assessments. RESULTS: Steady-state dapsone, NAD, and DHA concentrations were reached within 7 days of the first dose in all treatment groups. Daily systemic exposures of the 3 dapsone gel, 7.5% formulations were approximately 25% to 40% lower than that for dapsone gel, 5%, and these differences were statistically significant. Among the 3 dapsone gel, 7.5% formulations, the highest daily exposure of dapsone (per the AUC) was observed with DAP-11080, with respective Cmax and AUC0-24 being approximately 28.6% and 28.7% lower relative to dapsone gel, 5%. Most AEs were mild to moderate in intensity. The safety profiles for all 3 formulations of once-daily dapsone, 7.5% gel and twice-daily dapsone gel, 5% were similar following 28 days of topical administration. All 4 dapsone formulations were well tolerated. CONCLUSIONS: This study demonstrated lower systemic exposure with all 3 once-daily dapsone gel, 7.5% formulations than with twice-daily dapsone gel, 5%. All 4 formulations were well tolerated and demonstrated similar safety profiles.

J Drugs Dermatol. 2016;15(10):1250-1259.

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Effective treatment of acne vulgaris (acne) can improve patients’ qualify of life (QOL) and psychological well-being,1,2 both of which may be adversely affected by acne.1,3,4 While oral dapsone, a sulfone compound with anti-inflammatory properties,5-8 has been available for more than 60 years,9 topical dapsone gel, 5% (Aczone; Allergan plc, Dublin, Ireland) is approved for treatment of acne in the United States and Canada by the Food and Drug Administration (FDA) and Health Canada, respectively.10,11 Applied twice daily, dapsone gel, 5% has minimal systemic absorption, has a safety profile similar to vehicle, and has demonstrated clinical efficacy compared with vehicle, with improvement in acne severity by Global Acne Assessment Scores (GAAS) and in inflammatory and noninflammatory lesions.12,13 Additionally, a 14-day study showed that relative systemic exposure to dapsone and its primary metabolite, N-acetyl dapsone, was more than 100-fold less than exposure following daily administration of oral dapsone 100 mg.14While acne may require long-term treatment for effective management,15,16 adherence in the long-term setting may be affected by factors such as simplicity of treatment regimen, ease of use, and dosing interval.17-19 A once-daily formulation of dapsone gel would minimize dosing frequency and offer convenience and flexibility that may improve medication adherence compared with that of the twice-daily formulation.17-20 Allergan developed once-daily dapsone gel, 7.5%, with a simpler dosing regimen than twice-daily dapsone gel, 5%. Once-daily dapsone gel, 7.5% was safe, well tolerated, and efficacious for treatment of acne in 2, large, placebo-controlled, phase 3 studies.21,22 Based on these pivotal registration studies, dapsone gel, 7.5% was recently approved by the FDA for the once-daily treatment of acne vulgaris. Here, we present phase 1 study data that supported development of dapsone gel, 7.5%. The current study compared the pharmacokinetics (PK), safety, and tolerability of 3 formulations of once-daily dapsone gel, 7.5% with twice-daily dapsone gel, 5% in patients

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