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

Abstract

To evaluate the effect of lapatinib on the QTc interval and ECG parameters in patients with advanced solid tumors. This was a multicenter, placebo-controlled study in subjects with advanced solid tumors. Subjects were administered two doses of matching placebo on day 1, 12h apart and one dose in the morning on day 2. Two doses of lapatinib 2000mg were administered orally on day 3, 12h 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. A maximum mean baseline-adjusted, placebo time-matched increase in QTcF, (ddQTcF) in the evaluable, (EV) population (n = 37) of 8.8ms (90% CI 4.1, 13.4) occurred approximately 10h after the third lapatinib dose. These results were consistent with those in the pharmacodynamic, PD population, (n = 52) (ddQTcF = 7.9ms; 90% CI 4.1, 11.7). No subject experienced QTcF increases from baseline of > 60ms on lapatinib or placebo. The geometric mean lapatinib Cmax of 3902ng/mL was observed at 3.6h post-dose. These data show a relevant, treatment-related increase in QTcF after treatment with three doses of lapatinib 2000mg. 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.