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Effects of Subcutaneous Pasireotide on Cardiac Repolarization in Healthy Volunteers: A Single-Center, Phase I, Randomized, Four-Way Crossover Study

Breitschaft, A and Hu, K and Darstein, C and Ligueros-Saylan, M and Jordaan, P and Song, D and Hudson, M and Shah, R (2014) Effects of Subcutaneous Pasireotide on Cardiac Repolarization in Healthy Volunteers: A Single-Center, Phase I, Randomized, Four-Way Crossover Study. JOURNAL OF CLINICAL PHARMACOLOGY. pp. 75-86.

Abstract

The aim of this study was to evaluate the effects of subcutaneous pasireotide on cardiac repolarization in healthy volunteers. Healthy volunteers were randomized to one of four treatment sequences (n=112) involving four successive treatments in different order: pasireotide 600 mu g (therapeutic dose) or 1,950 mu g (maximum tolerated dose) bid by subcutaneous injection (sc), placebo injection and oral moxifloxacin. Maximum QTcI occurred 2 hours post-dose for both doses of pasireotide. Mean QTcI was 13.2milliseconds (90% CI: 11.4, 15.0) and 16.1milliseconds (90% CI: 14.3, 17.9) for the 600 and 1,950 mu g bid doses, respectively. Maximal placebo-subtracted change in QTcI from baseline for moxifloxacin was 11.1 (90% CI: 9.3, 12.9) milliseconds. Both pasireotide doses caused a reduction in heart rate: maximal heart rate change compared with placebo occurred at 1hour for pasireotide 600 mu g bid and at 0.5hours for pasireotide 1,950 mu g bid, with heart rate reductions of 10.4 and 14.9bpm, respectively. At the therapeutic dose of 600 mu g, pasireotide has a modest QT-prolonging effect. The relatively small increase of approximate to 3milliseconds in QTcI in the presence of a 3.25-fold increase in dose suggests a relatively flat dose-effect relationship of pasireotide on QTcI in healthy volunteers. No safety concerns for pasireotide were identified during the study

Item Type: Article
Additional Information: NIBR author: Jordaan, P institute: NIBR contributor address: Parexel Int GmbH, Klinikum Westend, Berlin, Germany astrid.breitschaft@parexel.com; Novartis Pharmaceut, E Hanover, NJ USA ; Novartis Pharma AG, Basel, Switzerland ; Novartis Inst BioMed Res, Basel, Switzerland ; Parexel Int GmbH, Klinikum Westend, Berlin, Germany; Breitschaft, A; Early Phase Clin Unit, Berlin Haus 31,Spandauer Damm 130, D-14050 Berlin, Germany
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22608

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