In vitro and clinical investigations to determine the drug-drug interaction potential of entrectinib, a small molecule inhibitor of neurotrophic tyrosine receptor kinase (NTRK)

Abstract

Background Entrectinib is a CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, ROS1 and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe the in vitro and clinical studies investigating potential entrectinib drug-drug interactions. Methods In vitro studies with human biomaterials assessed the enzymes involved in entrectinib metabolism, and whether entrectinib modulates the activity of the major cytochrome P450 (CYP) enzymes or drug transporter P-glycoprotein. Clinical studies investigated the effect of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on single-dose entrectinib pharmacokinetics. The effect of entrectinib on sensitive probe substrates for CYP3A4 (midazolam) and P-glycoprotein (digoxin) were also investigated. Results Entrectinib is primarily metabolized by CYP3A4. In vitro, entrectinib is a CYP3A4/5 inhibitor (IC50 2 μM) and a weak CYP3A4 inducer. Entrectinib inhibited P-glycoprotein (IC50 1.33 μM) but is a poor substrate. In healthy subjects, itraconazole increased entrectinib Cmax and AUC by 73% and 504%, respectively, and rifampin decreased entrectinib Cmax and AUC by 56% and 77%, respectively. Single dose entrectinib did not affect midazolam AUC, although Cmax decreased by 34%. Multiple dose entrectinib increased midazolam AUC by 50% and decreased Cmax by 21%. Single dose entrectinib increased digoxin AUC and Cmax by 18% and 28%, respectively, but did not affect digoxin renal clearance. Conclusions Entrectinib is a CYP3A4 substrate and is sensitive to the effects of coadministered moderate/strong CYP3A4 inhibitors and strong inducers, and requires dose adjustment. Entrectinib is a weak inhibitor of CYP3A4 and P-glycoprotein and no dose adjustments are required with CYP3A4/P- glycoprotein substrates.Registration Number (Study 2) NCT03330990 (first posted online November 6, 2017) As studies 1 and 3 are phase 1 trials in healthy subjects, they are not required to be registered.

Entrectinib—A SARS-CoV-2 Inhibitor in Human Lung Tissue (HLT) Cells

“…The most promising candidates were tested for their antiviral activities in a SARS-CoV-2 pseudovirus assay. Thereby, we identified two candidates, entrectinib (an inhibitor of tyrosine receptor kinases A/B/C, ROS1, and anaplastic lymphoma kinase [26]) and nilotinib (a Bcr-Abl tyrosine kinase inhibitor [27]), which showed similar viral entry blocking effects in vitro compared to the positive control apilimod (Figure 2).…”

Evaluation of the cytochrome P450 2C19 and 3A4 inhibition potential of the complement factor 5a receptor 1 antagonist ACT‐1014‐6470 in vitro and in vivo

“…Although 1-hydroxymidazolam concentrations significantly decreased after concomitant administration with some strong CYP3A4 inhibitors, 39,44,45 no or only modest effects on the metabolite's PK have been observed with other weak inhibitors. [46][47][48] The values in this study indicate that CYP3A4 inhibition by ACT-1014-6470 might be too weak to substantially affect the PK of the metabolite. T max (h) 0.8 (0.5, 1.5) 0.9 (0.3, 2.0) 0.9 (0.…”

Entrectinib Response to ROS1-Fusion-Positive Non-Small-Cell Lung Cancer That Progressed on Crizotinib with Leptomeningeal Metastasis: A Case Report

“…Indeed, the median OS of NSCLC patients with LM has been reported to be as short as 3.6–11 months [ 24 , 25 ]. P-gp, an important protein that actively transports drugs out of the blood-brain barrier, causes poor CNS efficacy [ 4 ]. Entrectinib is a weak P-gp substrate [ 3 ], in contrast to many other TKIs, including crizotinib.…”

“…The difference between these drugs is that entrectinib is a weak substrate with P-glycoprotein (P-gp) with a favorable brain distribution, whereas crizotinib is not [ 3 ]. P-gp is an essential efflux transporter located at the blood-brain barrier, and it transports out many drugs that are strong substrates of P-gp, leading to poor central nervous system (CNS) efficacy [ 4 ]. For that reason, the brain is a common first site of progression in NSCLC patients with ROS1 translocation who are taking crizotinib [ 5 ].…”