Dataset Information
Effect of inotuzumab ozogamicin on the QT interval in patients with haematologic malignancies using QTc-concentration modelling.
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ABSTRACT: 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.
SUBMITTER: Hibma JE
PROVIDER: S-EPMC6379221 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
Publications
Effect of inotuzumab ozogamicin on the QT interval in patients with haematologic malignancies using QTc-concentration modelling.
British journal of clinical pharmacology 20190121 3
<h4>Aim</h4>The aim of this study was to characterize the effect of inotuzumab ozogamicin on QT interval in patients with B-cell malignancies.<h4>Methods</h4>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<sup>-2</sup> per cycle in divided doses (mean C<sub>max</sub> 371 ng ml<sup>-1</sup> ; considered thera ...[more]