Sarecycline

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

The pharmacodynamics of sarecycline for the treatment of acne vulgaris are unknown.

Cardiac Electrophysiology

At approximately 3 times the maximum recommended dose, sarecycline did not prolong the QT interval to a clinically relevant extent.

Increasing the sarecycline dose from 60 to 150 mg once daily in healthy subjects resulted in a slightly less than proportional increase in sarcyeline steady-state C_max and AUC_tau. 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.

Absorption

The median time to peak plasma concentration (T_max) of sarecycline is 1.5 to 2.0 hours.

Effect of Food

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 T_max by approximately 0.53 hour and decreased sarecycline C_max by 31% and AUC by 27%.

Distribution

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.

Elimination

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

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.

Excretion

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).

Specific Populations

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.

Drug Interaction Studies

Clinical Studies

Coadministration of sarecycline with a combination oral contraceptive, ethinyl estradiol (EE) 20 mcg plus norethindrone (NE) acetate 1 mg, increased EE C_max by 14% and AUC_tau by 11%, and increased NE C_max by 18% and AUC_tau by 23%.

Coadministration of a single dose of sarecycline 150 mg resulted in a 26% increase in C_max of digoxin, a P-gp substrate.

In Vitro Studies

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.