The Effect of Verapamil, a P-gp Inhibitor, on the Pharmacokinetics, Safety, and Tolerability of Omadacycline in Healthy
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ORIGINAL RESEARCH ARTICLE
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. Hunt1 · Evan Tzanis2 · Stephen Bai2 · Amy Manley2 · Surya Chitra2 · Paul C. McGovern2
© The Author(s) 2020
Abstract Background 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. Objectives 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. Methods 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. Results 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 (AUC0–24), from time 0 to the last quantifiable concentration (AUC0–t), from time 0 extrapolated to infinity (AUC0–inf), and by maximum (peak) observed plasma concentration (Cmax). Treatment-emergent adverse events were reported by one participant (nausea and headache). Conclusions 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.
Key Points P-glycoprotein inhibitors have a small effect on the oral absorption of omadacycline. Based on the absence of safety concerns, dose adjustments for oral omadacycline are not required when administered with a known P-glycoprotein inhibitor. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13318-020-00651-3) contains supplementary material, which is available to authorized users. * Amy Manley [email protected] 1
PPD Phase 1 Clinic, 7551 Metro Center Drive, Suite 200, Austin, TX 78744, USA
Paratek Pharmaceuticals, Inc., 1000 First Avenue, Suite 200, King of Prussia, PA 19406, USA
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1 Introduction Omadacycline, a semisynthetic aminomethylcycline antibacterial derived from the tetracycline class [1], was approved in the USA in October 2018 to treat acute bacterial skin and skin-structure infections [2, 3] and community-acquired Vol.:(0123456789)
bacterial pneumonia (CABP) [4]. Omadacycline has shown favorable safety and tolerability profiles, demonstr
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