M. L. Zierhut, D. J. Nickens, W. Tan; Pfizer, San Diego, CA

**BACKGROUND:** Data from anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients enrolled in 2 Phase II/III clinical trials were used to examine the effect of crizotinib (CRZ) exposure on heart rate corrected QT interval (QTc).

**METHODS:** Patients orally received a recommended starting dose of 250 mg BID CRZ. In total, 405 paired CRZ concentrations (C) and electrocardiograms (ECG) were acquired at pre-specified times on days 1 and 22 from 62 patients. QT was corrected using Bazett’s (B), Fridericia’s (F) and a study specific (S) factor, β_{x}. Using pre-dose ECG data, β_{S} was estimated by: ln(QT) = ln(α) + β_{S}∙ln(RR) + ε; where ε~ N(0,σ), with α and σ also estimated. The relationship between C and RR or QTc was assessed using the following equation: Y = θ_{1} + η_{1} + (θ_{2} + η_{2})∙C + ε; where Y represents either RR or QTc, θ_{1} and θ_{2} are the intercept and slope, respectively, and η_{x} ~ N(0,ω_{x}).

**RESULTS:** A significant C-RR relationship was found, with a model predicted (90% confidence interval [CI]) change of 174 ms (142, 206) at the median observed maximum C (C_{max}) of 318 ng/mL. The slopes of QTc versus RR for the three factors were: B=-0.057, F=0.031, S=-0.002 ms/ms, presenting a bias in the estimation of drug induced changes in QTc. At C_{max}, the estimated biases based on the slopes from B, F and S were -9.9, +5.4 and -0.35 ms, respectively, indicating that QTcS best corrected for the effect of RR on QT. The analysis did not reveal a statistically significant C-QTcS relationship, and the model predicted (90% CI) change in QTcS at C_{max} was 2.99 ms (-0.118, 6.09).

**CONCLUSION:** Higher C was associated with higher RR. As a result, β_{B} and β_{F} led to more notable biases in the estimation of drug induced changes in QTc than β_{S} did. Based on C-QTcS modeling, no clinically relevant QT prolongation is expected at a CRZ dose level of 250 mg BID.