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

Abstract

1. Absorption, distribution, metabolism, transport and elimination properties of omadacycline, an aminomethylcycline antibiotic, were investigated in vitro and in a study in healthy male subjects.

2. Omadacycline was metabolically stable in human liver microsomes and hepatocytes and did not inhibit or induce any of the nine cytochrome P450 or five transporters tested. 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 [¹⁴C]-omadacycline (36.6 μCi). 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.

Keywords:

• Aminomethylcycline
• cytochrome P450
• human
• transporters

Acknowledgements

The authors would like to thank the Bioanalytics group (Novartis, East Hanover, NJ) for providing the omadacycline concentration data used in the pharmacokinetic analysis, and the Isotope Laboratory (Novartis, East Hanover, NJ) for providing radiolabeled drug substance and study doses.

Declaration of interest

The authors acknowledge the editorial assistance of Richard S. Perry, PharmD in the preparation of this manuscript, which was supported by Paratek Pharmaceuticals, King of Prussia, PA. Jimmy Flarakos, Yancy Du, Helen Gu, Lai Wang, Heidi J. Einolf, Dung Y. Chun, Bing Zhu, Natalia Alexander, Adrienne Natrillo, Imad Hanna, Lillian Ting, Wei Zhou, Kiran Dole, Haiying Sun, Steven J. Kovacs, Daniel S. Stein and James B. Mangold were employees of Novartis Institute for Biomedical Research at the time of these studies. SKT and SV are employees of Paratek Pharmaceuticals.

Supplementary material available online