Mass Balance and Drug Interaction Potential of Intravenous Eravacycline Administered to Healthy Subjects

• Published in: Antimicrobial agents and chemotherapy Vol. 63; no. 3
• Main Authors: Newman, Joseph V., Zhou, Jian, Izmailyan, Sergey, Tsai, Larry
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.03.2019
• Subjects: Adult; Anti-Bacterial Agents; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inducers - pharmacology; Cytochrome P-450 CYP3A Inhibitors - pharmacology; Drug Interactions; Female; Healthy Volunteers; Humans; Itraconazole - pharmacology; Male; Middle Aged; Pharmacology; Rifampin - pharmacology; Tetracyclines; Tetracyclines - adverse effects; Tetracyclines - pharmacokinetics; Tetracyclines - pharmacology; ADME; eravacycline; drug interaction
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.01810-18

Eravacycline is a novel, fully synthetic fluorocycline that is approved for the treatment of complicated intra-abdominal infections (cIAI) in adult patients. We report results from three studies in healthy subjects that investigated the distribution, metabolism, and excretion of intravenous (i.v.) eravacycline and the effect of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on the pharmacokinetics (PK) of i.v. Eravacycline is a novel, fully synthetic fluorocycline that is approved for the treatment of complicated intra-abdominal infections (cIAI) in adult patients. We report results from three studies in healthy subjects that investigated the distribution, metabolism, and excretion of intravenous (i.v.) eravacycline and the effect of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on the pharmacokinetics (PK) of i.v. eravacycline. In the mass balance study, the majority of total radioactivity from [ 14 C]eravacycline was recovered in the feces, suggesting biliary/fecal elimination is the major route of excretion for eravacycline and its metabolites after IV administration. The volume of distribution (217 liters) was greater than that of extracellular fluid, which suggests distribution beyond the central compartment. In the drug-drug interaction studies, mean area under the concentration-time curve from 0 h to the last time point (AUC 0 –t ) and half-life were increased approximately 30% to 40% after a concomitant dose of i.v. eravacycline and itraconazole and clearance (CL) was decreased. A reduction in total eravacycline exposure (AUC) of approximately 25% to 35% and an increase in CL of approximately 50% occurred with concomitant eravacycline and rifampin treatment. The dose of eravacycline should be increased to 1.5 mg/kg of body weight every 12 h when coadministered with a strong CYP3A inducer.