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Olaparib does not cause clinically relevant QT/QTc interval prolongation in patients with advanced solid tumours: results from two phase I studies
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Olaparib does not cause clinically relevant QT/QTc interval prolongation in patients with advanced solid tumours: results from two phase I studies
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Olaparib does not cause clinically relevant QT/QTc interval prolongation in patients with advanced solid tumours: results from two phase I studies
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Journal Article
Olaparib does not cause clinically relevant QT/QTc interval prolongation in patients with advanced solid tumours: results from two phase I studies
2016
Overview
Background
Some therapeutic agents in oncology can be causally associated with specific cardiovascular events including QT/QT
c
interval prolongation. We investigated the effect of multiple dosing of the oral poly (ADP-ribose)-polymerase (PARP) inhibitor, olaparib (tablet formulation) on QT/QT
c
interval.
Methods
Two phase I, open-label, three-part studies (NCT01921140 [study 4] and NCT01900028 [study 7]) were conducted in adults with refractory/resistant advanced solid tumours. In both studies, parts A and B assessed the QT/QT
c
interval effects of single-dose oral olaparib 100 (study 4) or 300 (study 7) mg and multiple-dose olaparib 300 mg bid for 5 days, respectively, while part C evaluated continued access to olaparib for additional safety analyses. An ANCOVA model tested the primary objective of multiple-dose effects of olaparib on QT interval corrected using Fridericia’s formula (QT
c
F).
Results
Data from 119 and 109 patients were pooled from parts A and B, respectively, for QT/QT
c
analysis. At pre-dose and up to 12 h post-dose, the upper limits of the 90 % confidence intervals (CIs) for the difference in QT
c
F least squares means after olaparib multiple dosing versus control (day −1) were <10 ms, suggesting a lack of clinically relevant effect on cardiac repolarization. A slight shortening of QT
c
F was observed at most time points versus control. QT
c
F results for the individual studies and single-dose olaparib paralleled the primary multiple-dose pooled analysis, with upper limits of the 90 % CIs < 10 ms.
Conclusion
Olaparib tablets administered as multiple or single doses had no clinically significant effect on QT/QT
c
interval.
Publisher
Springer Berlin Heidelberg
Subject
/ Aged
/ Dose-Response Relationship, Drug
/ Electrocardiography - drug effects
/ Female
/ Humans
/ Long QT Syndrome - chemically induced
/ Long QT Syndrome - epidemiology
/ Male
/ Medicine
/ Oncology
/ Phthalazines - administration & dosage
/ Phthalazines - adverse effects
/ Phthalazines - therapeutic use
/ Piperazines - administration & dosage
/ Piperazines - adverse effects
/ Piperazines - therapeutic use
/ Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage
