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.

Omadacycline Enters the Ring: A New Antimicrobial Contender

“…A mean plasma half‐life ( t 1/2 ) of 17 hours was observed, which was independent of formulation (tablet, solution, IV) for single‐dose administration . In a multiple‐dose evaluation, including dosages up to 600 mg, a 13‐hour t 1/2 was observed after single dose but was comparable to the previous study on day 5 (16 hrs) . Protein binding of omadacycline was low (20%) and nonspecific .…”

“…18 In a multiple-dose evaluation, including dosages up to 600 mg, a 13-hour t 1/2 was observed after single dose but was comparable to the previous study on day 5 (16 hrs). 17 Protein binding of omadacycline was low (20%) and nonspecific. 19 Omadacycline undergoes minimal hepatic metabolism and is neither a substrate, inducer, nor inhibitor of the cytochrome P450 system.…”

“…Pharmacokinetics of both oral and IV omadacycline have been evaluated in several clinical studies. Absolute bioavailability of omadacycline is 34.5%, leading to an oral dose of 300 mg versus a 100 mg IV dose . Omadacycline displays linear pharmacokinetics, with higher area under the curve (AUC) and maximum observed plasma concentrations ( C max ) with increasing dosages .…”

“…Absolute bioavailability of omadacycline is 34.5%, leading to an oral dose of 300 mg versus a 100 mg IV dose . Omadacycline displays linear pharmacokinetics, with higher area under the curve (AUC) and maximum observed plasma concentrations ( C max ) with increasing dosages . A mean plasma half‐life ( t 1/2 ) of 17 hours was observed, which was independent of formulation (tablet, solution, IV) for single‐dose administration .…”

“…17 Omadacycline displays linear pharmacokinetics, with higher area under the curve (AUC) and maximum observed plasma concentrations (C max ) with increasing dosages. 17 A mean plasma half-life (t 1/2 ) of 17 hours was observed, which was independent of formulation (tablet, solution, IV) for single-dose administration. 18 In a multiple-dose evaluation, including dosages up to 600 mg, a 13-hour t 1/2 was observed after single dose but was comparable to the previous study on day 5 (16 hrs).…”