title: Liposomes ameliorate Crizotinib- and Nilotinib-induced inhibition of the cardiac IKr channel and QTc prolongation.
abstract: Crizotinib (Xalkori®) and nilotinib (Tasigna®) are tyrosine kinase inhibitors approved for the treatment of non-small cell lung cancer and chronic myeloid leukemia, respectively. Both have been shown to result in electrocardiogram rate-corrected Q-wave T-wave interval (QTc) prolongation in humans and animals. Liposomes have been shown to ameliorate drug-induced effects on the cardiac-delayed rectifier K(+) current (IKr, KV11.1), coded by the human ether-a-go-go-related gene (hERG). This study was undertaken to determine if liposomes would also decrease the effect of crizotinib and nilotinib on the IKr channel. Crizotinib and nilotinib were tested in an in vitro IKr assay using human embryonic kidney (HEK) 293 cells stably transfected with the hERG. Dose-responses were determined and the 50% inhibitory concentrations (IC50s) were calculated. When the HEK 293 cells were treated with crizotinib or nilotinib that were mixed with liposomes, there was a significant decrease in the IKr channel inhibitory effects of these two drugs. When isolated, rabbit hearts were exposed to crizotinib or nilotinib, there were significant increases in QTc prolongation. Mixing either of the drugs with liposomes ameliorated the effects of the drugs. Rabbits dosed intravenously (IV) with crizotinib or nilotinib showed QTc prolongation. When liposomes were injected prior to crizotinib or nilotinib, the liposomes decreased the effects on the QTc interval. The use of liposomal encapsulated QT-prolongation agents, or giving liposomes in combination with drugs, may decrease their cardiac liability.
authors.affiliation: Shopp Nonclinical Consulting LLC, Boulder, CO, U.S.A.
authors.forename: George M
authors.initials: GM
authors.lastname: Shopp
authors.affiliation: SignPath Pharma, Quakertown, PA, U.S.A lhelson@comcast.net.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Helson
authors.affiliation: IPS Therapeutique Inc., Sherbrooke, QC, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Bouchard
authors.affiliation: IPS Therapeutique Inc., Sherbrooke, QC, Canada.
authors.forename: Dany
authors.initials: D
authors.lastname: Salvail
authors.affiliation: Sabinsa Corporation, East Windsor, NJ, U.S.A.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Majeed
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D000077547:Crizotinib; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects*; D006329:Heart Conduction System / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008081:Liposomes; D009206:Myocardium / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D011817:Rabbits
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D008081:Liposomes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D000077547:Crizotinib; C498826:nilotinib
keywords: Crizotinib; QT prolongation; cardiotoxicity; hERG; liposomes; nilotinib