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

Abstract

The absorption, distribution, metabolism, and excretion (ADME) 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 in male Long-Evans Hooded (LEH) rats. Following an intravenous (i.v.) dose of 5 mg/kg of body weight, radioactivity widely and rapidly distributed into most tissues. The highest tissue-to-blood concentration ratios (t/b) were observed in bone mineral, thyroid gland, and Harderian gland at 24 h post-i.v. dose. There was no evidence of stable accumulation in uveal tract tissue, suggesting the absence of a stable binding interaction with melanin. Following a 90 mg/kg oral dose in LEH rats, the highest t/b were observed in bone mineral, Harderian gland, liver, spleen, and salivary gland. The plasma protein binding levels were 26% in the rat and 15% to 21% in other species. Omadacycline plasma clearance was 1.2 liters/h/kg, and its half-life was 4.6 h; the steady-state volume of distribution (Vss) was 6.89 liters/kg. Major circulating components in plasma were intact omadacycline and its epimer. Consistent with observations in human, approximately 80% of the dose was excreted into the feces as unchanged omadacycline after i.v. administration. Fecal excretion was primarily the result of biliary excretion (∼40%) and direct gastrointestinal secretion (∼30%). However, urinary excretion (∼30%) was equally prominent after i.v. dosing.

Keywords: ADME; aminomethylcycline; animal models; omadacycline.

FIG 1

Mean concentrations of total radioactivity (quantified as nanogram equivalents per milliliter) in blood and plasma following a 90 mg/kg oral dose of ¹⁴C-omadacycline to Han/Wistar (HW) rats (n = 3).

FIG 2

Mean concentrations of omadacycline in rat plasma following a single i.v. dose of 5 mg/kg ¹⁴C-omadacycline or an oral dose of 90 mg/kg ¹⁴C-omadacycline to HW rats (n = 3).

FIG 3

Mean concentrations of total radioactivity in blood and plasma following a single 5 mg/kg i.v. dose of ¹⁴C-omadacycline to HW rats (n = 3).

FIG 4

Proposed metabolic scheme of ¹⁴C-omadacycline in the HW rats.

FIG 5

Chemical structures of ¹⁴C-omadacycline and the internal standard (C292H6H34N4O7).