The Effect of Verapamil, a P-gp Inhibitor, on the Pharmacokinetics, Safety, and Tolerability of Omadacycline in Healthy Adults: A Phase I, Open-Label, Single-Sequence Study
Thomas L. Hunt, Evan Tzanis, Stephen A. Bai, Amy Manley, Surya Chitra, Paul C. McGovern
Abstract
Omadacycline is a semisynthetic aminomethylcycline antibacterial derived from the tetracycline class. It is approved in the USA to treat adults with acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia. This phase I, open-label study evaluated the effect of a potential drug–drug interaction of verapamil—a known P-glycoprotein (P-gp) inhibitor—with omadacycline on the pharmacokinetic profile of omadacycline in healthy adults. The safety and tolerability of omadacycline taken alone and in combination with verapamil were also evaluated. A single oral dose of 240 mg verapamil extended release (ER) was given 2 h prior to a single oral dose of 300 mg omadacycline. Ten (83.3%) of the 12 participants enrolled in the study completed the study, and all enrolled participants were included in the safety and pharmacokinetic populations. An increase of 14–25% in systemic exposure to omadacycline was seen when administered following a single oral dose of 240 mg verapamil ER compared with omadacycline alone, as measured by the area under the concentration–time curve (AUC) from time 0 to 24 h after dosing (AUC 0–24 ), from time 0 to the last quantifiable concentration (AUC 0–t ), from time 0 extrapolated to infinity (AUC 0–inf ), and by maximum (peak) observed plasma concentration ( C max ). Treatment-emergent adverse events were reported by one participant (nausea and headache). These findings suggest that, if given with a known P-gp inhibitor, dose adjustment of oral omadacycline is not warranted based on small increases in absorption and systemic exposure. No safety signals were identified.