Aczone (Dapsone Topical) - Description and Clinical Pharmacology

DESCRIPTION

ACZONE™ Gel, 5%, contains dapsone, a sulfone, in an aqueous gel base for topical dermatologic use.  ACZONE™ Gel is a gritty, translucent material with visible drug substance particles. Chemically, dapsone has an empirical formula of C₁₂H₁₂N₂O₂S. It is a white, odorless crystalline powder that has a molecular weight of 248.  Dapsone’s chemical name is 4,4' - diaminodiphenylsulfone and its structural formula is:

Each gram of ACZONE™ (dapsone) Gel, 5%, contains 50 mg of dapsone, USP, in a gel of carbomer 980; diethylene glycol monoethyl ether, NF; methylparaben, NF; sodium hydroxide, USP; and purified water, USP.

CLINICAL PHARMACOLOGY

Mechanism of Action:

The mechanism of action of dapsone gel in treating acne vulgaris is not known.

Pharmacokinetics:

An open-label study compared the pharmacokinetics of dapsone after ACZONE™ Gel, 5%, (110 ± 60 mg/day) was applied twice daily (~BSA 22.5%) for 14 days (n=18) with a single 100 mg dose of oral dapsone administered to a subgroup of patients (n=10) in a crossover design.  On Day 14 the mean dapsone AUC_{0-24 h} was 415 ± 224 ng•h/mL for ACZONE™ Gel, 5%, whereas following a single 100 mg dose of oral dapsone the AUC_{0- infinity} was 52,641 ± 36,223 ng•h/mL.

Special Populations:

In a clinical study, periodic blood samples were collected up to 12 months to determine systemic exposure of dapsone and its metabolites in approximately 500 patients. Based on the measurable dapsone concentrations from 408 patients (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).

MICROBIOLOGY

In Vivo Activity:   No microbiology or immunology studies were conducted during dapsone gel clinical trials.

Drug Resistance:  No dapsone resistance studies were conducted during dapsone gel clinical trials. Therapeutic resistance to dapsone has been reported for Mycobacterium leprae, when patients have been treated with oral dapsone.*

*Matsuoka, M. A. Dec 2000.  Mycobacterium leprae isolate resistant to dapsone, rifampin, ofloxacin and sparfloxacin. Int J Lepr Other Mycobact Dis. 68(4):452-5.

CLINICAL STUDIES

Two randomized, double blind, vehicle controlled, clinical studies were conducted to evaluate ACZONE™ Gel, 5%, for the treatment of patients with acne vulgaris (N=1475 and 1525).  The studies were designed to enroll patients 12 years of age and older with 20 to 50 inflammatory and 20 to 100 non-inflammatory lesions at baseline.  In these studies patients applied either ACZONE™ Gel, 5%, or vehicle control twice daily for up to 12 weeks.   Efficacy was evaluated in terms of success on the Global Acne Assessment Score (no or minimal acne) and in the percent reduction in inflammatory, non-inflammatory, and total lesions.

The Global Acne Assessment Score was a 5-point scale as follows:

0. None: no evidence of facial acne vulgaris

1. Minimal: few non-inflammatory lesions (comedones) are present; a few inflammatory lesions (papules/pustules) may be present

2. Mild: several to many non-inflammatory lesions (comedones) are present; a few inflammatory lesions (papules/pustules) are present

3. Moderate: many non-inflammatory (comedones) and inflammatory lesions (papules/pustules) are present; no nodulo-cystic lesions are allowed

4. Severe: significant degree of inflammatory disease; papules/pustules are a predominant feature; a few nodulo-cystic lesions may be present; comedones may be present.

The success rates on the Global Acne Assessment Score (no or minimal acne) at Week 12 are presented in Table 1.

Table 1 - Success (No or Minimal Acne) on the Global Acne Assessment Score at Week 12

	Study 1*		Study 2*
	ACZONE™ N=699	Vehicle N=687	ACZONE™ N=729	Vehicle N=738
*Analysis excludes subjects classified with minimal acne at baseline
Subjects with No or Minimal Acne	291 (42%)	223 (32%)	253 (35%)	206 (28%)

Table 2 presents the mean percent reduction in inflammatory, non-inflammatory, and total lesions from baseline to Week 12.

Table 2 - Percent Reduction in Lesions from Baseline to Week 12

	Study 1		Study 2
	ACZONE™ N=745	Vehicle N=740	ACZONE™ N=761	Vehicle N=764
Inflammatory	46%	42%	48%	40%
Non-Inflammatory	31%	24%	30%	21%
Total	38%	32%	37%	29%

The clinical studies enrolled about equal proportions of male and female subjects.  Female patients tended to have greater percent reductions in lesions and greater success on the Global Acne Assessment Score than males.  The breakdown by race in the clinical studies was about 73% Caucasian, 14% Black, 9% Hispanic, and 2% Asian.  Efficacy results were similar across the racial subgroups.