Source: FDA, National Drug Code (US) Revision Year: 2020
The mechanism of action of SEYSARA in treating acne vulgaris is not known.
The pharmacodynamics of SEYSARA for the treatment of acne vulgaris are unknown.
At approximately 3 times the maximum recommended dose, SEYSARA did not prolong the QT interval to a clinically relevant extent.
Increasing the SEYSARA dose from 60 to 150 mg once daily in healthy subjects resulted in a slightly less than proportional increase in sarcyeline steady-state Cmax and AUCtau. A mean accumulation ratio of sarecycline ranges from 1.5 to 1.6 fold with repeated dosing. Steady-state of sarecycline was reached by Day 7.
The median time to peak plasma concentration (Tmax) of sarecycline is 1.5 to 2.0 hours.
Coadministration with a high-fat (approximately 50% of total caloric content of the meal), high-calorie (800 to 1000 Kcal) meal that included milk delayed Tmax by approximately 0.53 hour and decreased sarecycline Cmax by 31% and AUC by 27%.
Protein binding of sarecycline is 62.5% to 74.7% in vitro. The mean apparent volume of distribution of sarecycline at steady-state ranges from 91.4 L to 97.0 L.
The mean apparent oral clearance (CL/F) of sarecycline at steady state is approximately 3 L/h. The mean elimination half-life of sarecycline is 21 to 22 hours.
Metabolism of sarecycline by enzymes in human liver microsomes is minimal (< 15%) in vitro. Minor metabolites resulting from non-enzymic epimerization, O-/N-demethylation, hydroxylation, and desaturation have been found.
After a single 100 mg oral dose of radiolabeled sarecycline, 42.6% of the dose was recovered in feces (14.9% as unchanged) and 44.1% in urine (24.7% as unchanged).
No clinically significant differences in the pharmacokinetics of sarecycline were observed based on age (11 to 73 years), weight (42 to 133 kg), sex, renal impairment, or mild to moderate hepatic impairment (Child Pugh A to B). The effect of end-stage renal disease (ESRD) or severe hepatic impairment (Child-Pugh C) on sarecycline pharmacokinetics has not been assessed.
Coadministration of SEYSARA with a combination oral contraceptive, ethinyl estradiol (EE) 20 mcg plus norethindrone (NE) acetate 1 mg, increased EE Cmax by 14% and AUCtau by 11%, and increased NE Cmax by 18% and AUCtau by 23%.
Coadministration of a single dose of SEYSARA 150 mg resulted in a 26% increase in Cmax of digoxin, a P-gp substrate.
Sarecycline is not a substrate for P-gp, BCRP, OATP1B1, or OATP1B3.
Sarecycline is a P-gp inhibitor. Sarecycline does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 isozymes, and does not inhibit OATP1B1, OATP1B3, OCT2, OAT1, OAT3, or BCRP.
Sarecycline does not induce CYP1A2, CYP2B6, or CYP3A4/5 isozymes.
Sarecycline is active in vitro against most isolates of Propionibacterium acnes; however, the clinical significance is unknown.
P. acnes strains displayed a low propensity for the development of resistance to sarecycline, with spontaneous mutation frequencies being 10-10 at 4-8 × MIC.
In a 2-year oral mouse carcinogenicity study and a 2-year oral rat carcinogenicity study, no drug-related neoplasms were observed in male mice at oral doses of sarecycline up to 100 mg/kg/day (approximately equal to the MRHD based on AUC comparison) or in female mice at doses up to 60 mg/kg/day (approximately equal to the MRHD based on AUC comparison), or in rats at doses up to 200/100 mg/kg/day (dose reduced from 200 to 100 mg/kg/day due to increased mortality; 8 times the MRHD based on AUC comparison).
Sarecycline was not mutagenic or clastogenic in a series of in vitro and in vivo genotoxicity studies, including a bacteria reverse mutation (Ames) assay, an in vitro chromosomal aberration assay in CHO cells, the L5178Y/TK+/- Mouse Lymphoma Assay, and an in vivo micronucleus assay in rats.
In a fertility and early embryonic development study in rats, sarecycline was administered to both male and female rats at oral doses up to 400 mg/kg/day prior to pairing and through the mating and postmating period. Female fertility was not affected at doses up to 400 mg/kg/day (8 times the MRHD based on AUC comparison). In sperm evaluation, decreased sperm motility, decreased sperm count and concentration, and an increase in percent abnormal sperm occurred at 400 mg/kg/day (8 times the MRHD based on AUC comparison). Male fertility was not affected at doses up to 150 mg/kg/day (4 times the MRHD based on AUC comparison).
The safety and efficacy of once daily SEYSARA was assessed in two 12-week multicenter, randomized, double-blind, placebo-controlled studies (Study 1 [NCT02320149] and Study 2 [NCT02322866]). Efficacy was assessed in a total of 2002 subjects 9 years of age and older. Overall, 57% were female, 78% were Caucasian, 15% were Black or African American and 51% were adults (18 to 45 years of age). Subjects were randomized to receive either SEYSARA or placebo once daily.
The two co-primary efficacy endpoints were:
The results at Week 12 are presented in the following table.
Table 2. Clinical Efficacy of SEYSARA at Week 12:
| Study 1 | Study 2 | |||
|---|---|---|---|---|
| SEYSARA (N=483) | Placebo (N=485) | SEYSARA (N=519) | Placebo (N=515) | |
| Investigator’s Global Assessment | ||||
| IGA Success | 21.9% | 10.5% | 22.6% | 15.3% |
| Inflammatory Lesions | ||||
| Mean absolute reduction | 15.3 | 10.2 | 15.5 | 11.1 |
| Mean percent reduction | 52.2% | 35.2% | 50.8% | 36.4% |
Mean absolute and percent reduction in inflammatory lesions was also greater with SEYSARA compared to placebo at Weeks 3, 6, and 9 for both studies.
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