Pharmacokinetics, Distribution, Metabolism and Excretion of Omadacycline Following a Single Intravenous or Oral Dose of 14C-omadacycline in Rats

Abstract

The pharmacokinetics, absorption, distribution, metabolism and excretion of Omadacycline, a first in class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive, Gram-negative, anaerobic, and atypical bacteria, were evaluated in rats. Tissue distribution was investigated by quantitative whole-body autoradiography (QWBA) in male Long Evans Hooded (LEH) rats. Following a 5 mg/kg IV dose, radioactivity widely and rapidly distributed into most tissues. The highest tissue-to-blood ratio was observed in bone mineral, thyroid gland, and harderian gland at 24 h post IV dose. There was no evidence of stable accumulation in uveal tract tissue suggesting no stable binding interaction with melanin. Following a 90 mg/kg oral dose in LEH rats, the highest tissue-to-blood ratios (t/b) were observed in bone mineral, harderian gland, liver, spleen, and salivary gland. Plasma protein binding was moderate in rat (26%) and other tested species (15% - 21%). Omadacycline plasma clearance and half-life was estimated to be moderate (1.2 L/h/kg and 4.6 h); steady-state volume of distribution (Vss) was estimated to be large (6.89 L/kg). Major circulating components in plasma were intact omadacycline and its epimer. Consistent with observations in human, fecal and urine excretion was the main route of elimination in rat . Approximately 80% of the dose was excreted into the feces as unchanged omadacycline after intravenous administration. Fecal excretion was primarily the result of biliary excretion (~40%) and direct gastrointestinal secretion (~30%). However, urinary excretion (~30%) was equally prominent after IV dosing. Omadacycline can be categorized as a preliminary Biopharmaceutics Drug Disposition Classification System (BDDCS) III drug given its extensive excretion in vivo, low absorption, low lipophilicity and high aqueous solubility