Liposomes Ameliorate Crizotinib- and Nilotinib-induced Inhibition of the Cardiac Ikr Channel and QTc Prolongation

ANTICANCER RESEARCH 34: 4733-4740 (2014)

Liposomes Ameliorate Crizotinib- and Nilotinib-induced
Inhibition of the Cardiac IKr Channel and QTc Prolongation

GEORGE M. SHOPP1, LAWRENCE HELSON2, ANNIE BOUCHARD3,
DANY SALVAIL3 and MUHAMMAD MAJEED4
1Shopp Nonclinical Consulting LLC, Boulder, CO, U.S.A.;
2SignPath Pharma, Quakertown, PA, U.S.A;
3IPS Therapeutique Inc., Sherbrooke, QC, Canada;
4Sabinsa Corporation, East Windsor, NJ, U.S.A.

Abstract. Crizotinib (Xalkori®) and nilotinib (Tasigna®) are
tyrosine kinase inhibitors approved for the treatment of nonsmall
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 cardiacdelayed
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.

This article is freely accessible online.

Correspondence to: Lawrence Helson, MD SignPath Pharma, 1375
California Road, Quakertown PA 18951, U.S.A. Tel: +1
2155389996, Fax: +1 2155381245, e-mail: lhelson@comcast.net

Key Words: Crizotinib, nilotinib, liposomes, hERG, QT
prolongation, cardiotoxicity.