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

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 (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). 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. Electronic supplementary material The online version of this article (10.1007/s13318-020-00651-3) contains supplementary material, which is available to authorized users.

Intestinal absorption pathways of lisinopril: Mechanistic investigations

“…Verapamil was utilized in this study to confirm the contribution of P‐gp efflux transporters to poor lisinopril permeability. According to the FDA guidance recommendation, verapamil was reported as a potential P‐gp inhibitor (Hunt et al., 2021; Wang & Sun, 2020). The influence of coperfusion of verapamil on lisinopril absorption was investigated in the duodenum and ileum segments.…”

“…It may exert its action via modulating intestinal membrane dynamics and permeability characteristics facilitating drug absorption through the intestinal barrier (Gohil & Mehta, 2009; Khajuria et al., 1998, 2002). Verapamil was selected due to its reported P‐gp inhibitory effect (Hunt et al., 2021; Wang & Sun, 2020). This may aid in investigating the contributing role of P‐gp efflux transporter in limited lisinopril permeability.…”

“…Verapamil was selected due to its reported P-gp inhibitory effect (Hunt et al, 2021;Wang & Sun, 2020). This may aid in investigating the contributing role of P-gp efflux transporter in limited lisinopril permeability.…”

Potential Pharmacokinetic Effect of Chicken Xenobiotic Receptor Activator on Sulfadiazine: Involvement of P-glycoprotein Induction

“…The primary hepatocytes of chicken embryo inoculated in 24-well plates were cultured to about 80% confluency. Cells were treated with metyrapone (500 μM) alone or combined with 100 μM verapamil, a specific P-gp inhibitor [ 32 , 33 , 34 ], for 24 h, and cells without treatment were used as the control. The cells were washed twice with PBS and then incubated with 5 μM Rho123, a selective P-gp substrate [ 35 , 36 , 37 ], for 60 min.…”

Downregulation of MACC1 facilitates the reversal effect of verapamil on the chemoresistance to active metabolite of irinotecan in human colon cancer cells

“…VER at concentrations of 6.0–10.0 μmol/L exerts effective reversal effect on tumor drug resistance and can improve the clinical efficacy of chemotherapy for hepatocellular cancer, colon cancer, lung cancer, and malignant ascites ( Liu et al., 2011 ). Studies have shown that the reversal effect mechanism of VER in MDR in tumors is likely related to P-glycoprotein (P-gp) ( Gao et al., 2021 ; Hunt et al., 2021 ). VER resists MDR in tumors by regulating the expression of P-gp.…”