Effect of inotuzumab ozogamicin on the QT interval in patients with haematologic malignancies using QTc-concentration modelling.

AIM: The aim of this study was to characterize the effect of inotuzumab ozogamicin on QT interval in patients with B-cell malignancies.

METHODS

Data were pooled from three clinical studies including 250 patients (n = 2743) who received inotuzumab ozogamicin monotherapy. Patients with relapsed/refractory acute lymphoblastic leukaemia (NCT01564784 and NCT01363297) received 1.8 mg m-2 per cycle in divided doses (mean Cmax 371 ng ml-1 ; considered therapeutic) and patients with relapsed/refractory non-Hodgkin lymphoma (NCT00868608) received 1.8 mg m-2 per cycle as a single dose (mean Cmax 569 ng ml-1 ; considered supratherapeutic). Triplicate 12-lead electrocardiograms were performed at baseline and predefined time points postdose with paired pharmacokinetic collections. The exposure-response relationship between corrected QT interval (QTc: QT interval corrected using population-specific formula [QTcS] or QT interval corrected using Fridericia's formula [QTcF]) and inotuzumab ozogamicin concentration was characterized using a linear mixed-effects model, and simulations were performed using the final validated model. Full model development involved testing for covariates that may account for part of the identified variability.

RESULTS

QTc intervals had a small but positive correlation with inotuzumab ozogamicin concentration. Based on 1000 simulations, median (upper 95% CI) QTcS and QTcF changes from baseline were <10 ms at both therapeutic (2.70 ms [5.40 ms] and 2.53 ms [4.92 ms], respectively) and supratherapeutic (4.14 ms [8.28 ms] and 3.87 ms [7.54 ms], respectively) concentrations.

CONCLUSIONS

Inotuzumab ozogamicin (1.8 mg m-2 per cycle) is not predicted to pose a clinically significant safety risk for QT prolongation in patients with acute lymphoblastic leukaemia or non-Hodgkin lymphoma.