Omadacycline: A Review of the Clinical Pharmacokinetics and Pharmacodynamics.

Omadacycline is a novel aminomethylcycline antibiotic (antibacterial). Omadacycline has had chemical structure modifications at the C9 and C7 positions of the core tetracycline rings that allow stability in the efflux pump and ribosomal protection protein mechanisms of tetracycline resistance. The systemic exposure (i.e., maximum plasma concentrations [Cmax] and area under the plasma concentration-time curve [AUC]) after intravenous (IV) administration were linear and predictable over the dose range of 25 and 600 mg in healthy subjects. The oral bioavailability of omadacycline was 34.5% under fasted conditions (no food intake 6 h before and 4 h after dosing). Both AUC and Cmax values significantly decreased (41-61%) when a high-fat meal, with and without dairy, were administered 2 h before oral dosing of omadacycline. Similar to other tetracyclines, it is advisable to avoid concurrent administration of divalent- or trivalent cation-containing products (e.g., antacids and iron-containing preparations) for at least 4 h after oral administration of omadacycline. Omadacycline has a large volume of distribution (190 L) and low plasma protein binding (21.3%) that was concentration independent. Systemic exposure of omadacycline in epithelial lining fluid (ELF) and alveolar macrophages was greater than in plasma in healthy adult subjects. Omadacycline is excreted unchanged in the feces (81.1%) and urine (14.4%), and has a low potential for drug-drug interactions since it was not a substrate, inhibitor, or inducer of major cytochrome-metabolizing enzymes or organic anion transporters (OATs). No clinically significant differences in the pharmacokinetics of omadacycline have been observed for age, sex, and renal or hepatic impairment. Pharmacokinetic-pharmacodynamic studies have confirmed that the AUC from time zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) ratio was the best index for correlating unbound plasma and total-drug ELF concentrations with the efficacy of omadacycline. A population pharmacokinetic model was developed with data from healthy subjects and infected patients and used to establish interpretive criteria for in vitro susceptibility testing and dosing regimens of omadacycline for treating acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia.