Clinical disposition, metabolism and in vitro drug–drug interaction properties of omadacycline

Abstract

(2017) Clinical disposition, metabolism and invitro drug-drug interaction properties of omadacycline, Xenobiotica, 47:8, 682-696, DOI: 10.1080/00498254.2016 Omadacycline was a substrate of P-glycoprotein, but not of the other transporters. 3. Omadacycline metabolic stability was confirmed in six healthy male subjects who received a single 300 mg oral dose of [ 14 C]-omadacycline (36.6 mCi). Absorption was rapid with peak radioactivity ($610 ngEq/mL) between 1-4 h in plasma or blood. The AUC last of plasma radioactivity (only quantifiable to 8 h due to low radioactivity) was 3096 ngEq h/mL and apparent terminal half-life was 11.1 h. Unchanged omadacycline reached peak plasma concentrations ($563 ng/mL) between 1-4 h. Apparent plasma half-life was 17.6 h with biphasic elimination. Plasma exposure (AUC inf ) averaged 9418 ng h/mL, with high clearance (CL/F, 32.8 L/h) and volume of distribution (Vz/F 828 L). No plasma metabolites were observed. 4. Radioactivity recovery of the administered dose in excreta was complete (>95%); renal and fecal elimination were 14.4% and 81.1%, respectively. No metabolites were observed in urine or feces, only the omadacycline C4-epimer.

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

“…The oral bioavailability was very low (0.23%) compared to the absorption (Table 4), suggesting significant first-pass elimination. The oral bioavailability was much lower than ∼35% in humans (5). …”

“…administration and high concentrations in small intestine after oral administration. In humans, bioavailability was estimated to be approximately 35% (5). In contrast to humans and monkeys, rats lack gallbladder organs; therefore, bile flow in rats is continuous.…”

“…therapy for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). The microbiological activity, pharmacokinetic profile, and potential clinical efficacy and tolerability of omadacycline in preclinical and phase 1 and phase 2 clinical studies have been described previously (1–5). …”

Managing community acquired pneumonia in the elderly – the next generation of pharmacotherapy on the horizon

“…Pharmacodynamically, it is highly potent, having a three to five times lower MIC90 than vancomycin and linezolid for tetracycline sensitive staphylococcus species, and having a nine times lower MIC90 for MRSA and other resistant strains. 37 …”

“…37 Second, it does not interact with the cytochrome P450 isoenzymes and is minimally protein bound in the serum and thus has few medication interactions. 37 Although there are few reports of severe side-effects, overall minor side-effects are relatively common, with nausea and headache being the most common. Third, it does however have a strong PD profile, being highly potent especially against resistant CAP pathogens.…”