title: Randomized, Open-Label Study of the Pharmacokinetics and Safety of Oral and Intravenous Administration of Omadacycline to Healthy Subjects.
abstract: Omadacycline is a first-in-class aminomethylcycline antibiotic with microbiological activity against Gram-positive and Gram-negative aerobes and anaerobes and atypical bacteria that is being developed for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). The bioavailability of a phase 3 tablet formulation relative to that obtained via intravenous (i.v.) administration (and of other oral formulations relative to that of the phase 3 tablet) was investigated in an open-label, randomized, four-period, crossover study with healthy subjects age 18 to 50 years. Subjects received omadacycline at 100 mg i.v., 300 mg orally as two different tablet formulations with different dissolution profiles, and 300 mg as an oral solution. Plasma omadacycline concentrations were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Twenty of 24 subjects completed all treatment periods. The two tablet formulations produced equivalent total exposures. The phase 3 tablet produced an exposure equivalent to that of the 100-mg i.v. dose, with a geometric mean ratio (90% confidence intervals [CI]) for area under the concentration-time curve from 0 h to infinity [AUC∞]) of 1.00 (0.93, 1.07). The absolute bioavailability of the tablets was approximately 34.5%. Intersubject variability was consistent among the oral formulations (∼20 to 25%). Single oral and i.v. doses of omadacycline were well tolerated; three subjects experienced mild adverse events (dizziness, nausea, and vomiting) that resolved without intervention. A 300-mg dose of the tablet formulation of omadacycline intended for use in phase 3 studies produced a total exposure equivalent to that of a 100-mg i.v. dose.
authors.affiliation: Novartis Institute for Biomedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Sun
authors.affiliation: Novartis Institute for Biomedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey, USA.
authors.forename: Lillian
authors.initials: L
authors.lastname: Ting
authors.affiliation: Novartis Healthcare, Ltd., Hyderabad, India.
authors.forename: Surendra
authors.initials: S
authors.lastname: Machineni
authors.affiliation: Novartis Institute for Biomedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Praestgaard
authors.affiliation: Novartis Institute for Biomedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuemmell
authors.affiliation: Novartis Institute for Biomedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Stein
authors.affiliation: Novartis Institute for Biomedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey, USA.
authors.forename: Gangadhar
authors.initials: G
authors.lastname: Sunkara
authors.affiliation: Novartis Institute for Biomedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kovacs
authors.affiliation: Paratek Pharmaceuticals, Boston, Massachusetts, USA stephen.villano@paratekpharma.com.
authors.forename: Stephen
authors.initials: S
authors.lastname: Villano
authors.affiliation: Paratek Pharmaceuticals, Boston, Massachusetts, USA.
authors.forename: S Ken
authors.initials: SK
authors.lastname: Tanaka
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D013607:Tablets; D053719:Tandem Mass Spectrometry; D013754:Tetracyclines / Q000097:blood / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency
chemical_list: D000900:Anti-Bacterial Agents; D013607:Tablets; D013754:Tetracyclines; C000591640:omadacycline