Safety and Pharmacokinetics of the Aminomethylcycline Antibiotic Omadacycline Administered to Healthy Subjects in Oral Multiple-Dose Regimens

Abstract

Omadacycline, a first-in-class aminomethylcycline antibiotic, is related to tetracyclines but is structurally modified to circumvent mechanisms of resistance to tetracyclines. Omadacycline demonstrates potent activity against a broad range of pathogens, including drug-resistant strains, and is in late-stage development for treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Previous studies support an intravenous-to-oral transition regimen with 300-mg once-daily oral dosing. This phase 1 study investigated the pharmacokinetics and safety/tolerability of multiple oral omadacycline doses higher than 300 mg. Using a 3-period crossover design, healthy adults were randomized to receive oral omadacycline at 300, 450, and 600 mg in variable sequence (n = 26) or placebo (n = 7) once daily for 5 consecutive days per period. In plasma, omadacycline maximum concentration and total exposure increased with increasing dose but were less than dose proportional. The kinetics of omadacycline plasma accumulation were similar between dose levels; exposure on day 5 was ∼50% higher than that on day 1. Omadacycline plasma concentrations on day 1 of 450-mg dosing were similar to those on day 5 of 300-mg dosing. All doses were generally well tolerated, but the 600-mg dose was associated with more gastrointestinal adverse events.

Keywords: multidose regimen; omadacycline; oral dosing.

FIG 1

Plasma concentration-versus-time curves of omadacycline after oral administration. Mean (±SD) plasma concentrations of omadacycline versus time are shown by omadacycline dose group (300, 450, or 600 mg) for the PK population. Oral omadacycline doses were administered at time zero on each of 5 consecutive days of dosing in each of 3 periods. Blood samples were collected for PK analysis on day 1 (left) and day 5 (right). Data were pooled by omadacycline dose for all subjects regardless of the period in which they received a particular dose. SD, standard deviations.