BACKGROUND: Some therapeutic agents in oncology can be causally associated with specific cardiovascular events including QT/QTc interval prolongation. We investigated the effect of multiple dosing of the oral poly (ADP-ribose)-polymerase (PARP) inhibitor, olaparib (tablet formulation) on QT/QTc 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/QTc 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 (QTcF). RESULTS: Data from 119 and 109 patients were pooled from parts A and B, respectively, for QT/QTc analysis. At pre-dose and up to 12 h post-dose, the upper limits of the 90 % confidence intervals (CIs) for the difference in QTcF 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 QTcF was observed at most time points versus control. QTcF 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/QTc interval.
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BACKGROUND: Some therapeutic agents in oncology can be causally associated with specific cardiovascular events including QT/QTc interval prolongation. We investigated the effect of multiple dosing of the oral poly (ADP-ribose)-polymerase (PARP) inhibitor, olaparib (tablet formulation) on QT/QTc 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/QTc 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 (QTcF). RESULTS: Data from 119 and 109 patients were pooled from parts A and B, respectively, for QT/QTc analysis. At pre-dose and up to 12 h post-dose, the upper limits of the 90 % confidence intervals (CIs) for the difference in QTcF 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 QTcF was observed at most time points versus control. QTcF 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/QTc interval.
Authors: Gottfried E Konecny; Amit M Oza; Anna V Tinker; Ana Oaknin; Ronnie Shapira-Frommer; Isabelle Ray-Coquard; Carol Aghajanian; Robert L Coleman; David M O'Malley; Alexandra Leary; Lee-May Chen; Diane Provencher; Ling Ma; James D Brenton; Cesar Castro; Michelle Green; Andrew D Simmons; Jeri Beltman; Thomas Harding; Kevin K Lin; Sandra Goble; Lara Maloney; Rebecca S Kristeleit; Iain A McNeish; Elizabeth M Swisher; Jim J Xiao Journal: Gynecol Oncol Date: 2021-03-19 Impact factor: 5.304
Authors: Deli Zhang; Xu Hu; Jin Li; Jia Liu; Luciënne Baks-Te Bulte; Marit Wiersma; Noor-Ul-Ann Malik; Denise M S van Marion; Marziyeh Tolouee; Femke Hoogstra-Berends; Eva A H Lanters; Arie M van Roon; Antoine A F de Vries; Daniël A Pijnappels; Natasja M S de Groot; Robert H Henning; Bianca J J M Brundel Journal: Nat Commun Date: 2019-03-21 Impact factor: 14.919