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01-08-2019 | Solid Tumor | Original Article

The effects of lapatinib on cardiac repolarization: results from a placebo controlled, single sequence, crossover study in patients with advanced solid tumors

Authors: Shodeinde A. Coker, Herbert I. Hurwitz, Sunil Sharma, Ding Wang, Pierre Jordaan, Juan Pablo Zarate, Lionel D. Lewis

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2019

Abstract

Purpose

To evaluate the effect of lapatinib on the QTc interval and ECG parameters in patients with advanced solid tumors.

Methods

This was a multicenter, placebo-controlled study in subjects with advanced solid tumors. Subjects were administered two doses of matching placebo on day 1, 12 h apart and one dose in the morning on day 2. Two doses of lapatinib 2000 mg were administered orally on day 3, 12 h apart and one dose in the morning on day 4. Twelve-lead digital ECGs were extracted from continuous Holter recordings at pre-specified time points over the 24-h period on days 2 and 4. Venous blood samples for lapatinib concentrations were obtained immediately following the ECGs.

Results

A maximum mean baseline-adjusted, placebo time-matched increase in QTcF, (ddQTcF) in the evaluable, (EV) population (n = 37) of 8.8 ms (90% CI 4.1, 13.4) occurred approximately 10 h after the third lapatinib dose. These results were consistent with those in the pharmacodynamic, PD population, (n = 52) (ddQTcF = 7.9 ms; 90% CI 4.1, 11.7). No subject experienced QTcF increases from baseline of > 60 ms on lapatinib or placebo. The geometric mean lapatinib C_max of 3902 ng/mL was observed at 3.6 h post-dose.

Conclusions

These data show a relevant, treatment-related increase in QTcF after treatment with three doses of lapatinib 2000 mg. This study confirms the need for caution in patients with solid tumors treated with lapatinib, and who are concomitantly receiving drugs that are strong CYP3A inhibitors and/or prolong the QTc.

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Title: The effects of lapatinib on cardiac repolarization: results from a placebo controlled, single sequence, crossover study in patients with advanced solid tumors
Authors: Shodeinde A. Coker
Herbert I. Hurwitz
Sunil Sharma
Ding Wang
Pierre Jordaan
Juan Pablo Zarate
Lionel D. Lewis
Publication date: 01-08-2019
Publisher: Springer Berlin Heidelberg
Keywords: Solid Tumor
Lapatinib
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03880-9

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