Repeated supratherapeutic dosing of strontium ranelate over 15days does not prolong QTc interval in healthy volunteers

• Published in: British journal of clinical pharmacology Vol. 74; no. 2; pp. 296 - 303
• Main Authors: Taubel, Jorg, Naseem, Asif, Wang, Duolao, Arezina, Radivoj, Lorch, Ulrike, Camm, AJohn
• Format: Journal Article
• Language: English
• Published: 01.08.2012
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2012.04190.x

times Strontium ranelate 2g (granule form) oral suspension, is an anti-osteoporotic treatment which is available in European countries. times Repeated administration of strontium ranelate (4gday-1) was found to be clinically and biologically well tolerated by healthy post menopausal women volunteers. times Strontium is a bivalent cation with strong affinity for bone and which in certain conditions has a metabolism similar to that of calcium. In terms of importance, calcium has a major role in the electrophysiology of cardiac muscle and ECG abnormalities are known to be due to changes in plasma calcium concentrations. times Although no signal was observed in pre-clinical or clinical studies, the safety of strontium ranelate in accordance with the ICH - E14 guidelines needed to be assessed in order to characterize the effect on QTc of repeated oral doses of strontium ranelate (4gday-1). WHAT THIS STUDY ADDS times This thorough QT/QTc study directly compared supratherapeutic repeat doses of strontium ranelate (4gday-1 for 15days) with placebo on the largest time-matched mean QTc variation (from baseline to under treatment values) in healthy subjects. times Supratherapeutic (4gday-1) repeated doses of strontium ranelate did not produce any clinically significant prolongation in QTc. times The findings of this study clearly indicate that administration of strontium ranelate at the therapeutic dose of 2g will not cause prolongation of QT that is of any clinical concern. AIMS The study was performed to assess the safety of strontium ranelate in accordance with the ICH, E14 guidelines for QT/QTc studies. Its primary objective was to compare supratherapeutic repeated dosing of strontium ranelate (4gday-1 for 15days) with placebo on the largest time-matched mean QTc variation, from baseline to under treatment values, in healthy subjects. METHODS Ninety-six healthy male and female subjects (27.7 plus or minus 7.5years) were included to receive 1day of placebo followed by 15days of supratherapeutic repeated dosing of strontium ranelate (4gday-1), in a 4month, randomized, placebo (16days) and positive-controlled (single dose of moxifloxacin 400mg preceded by 15days of placebo), double-blind, double dummy, crossover design. Measurement of QT interval was performed automatically on the ECGs with subsequent manual onscreen over-reading by cardiologists using electronic callipers. RESULTS The largest time-matched difference in QTcI (individual QT correction for heart rate) between moxifloxacin 400mg and placebo was observed at 2h post dose (mean [95% CI] 10.62 [7.90, 13.35] ms). For strontium ranelate (4gday-1) the largest time-matched difference in QTcI compared with placebo was observed at 1h post dose (mean [90% CI] 7.54 [5.17, 9.90] ms). No subject had a QTc greater than 480ms during the study. Both moxifloxacin and strontium ranelate were well tolerated in healthy subjects. CONCLUSIONS The findings of this study demonstrate that the administration of supratherapeutic repeated oral doses of strontium ranelate (4gday-1 for 15days) does not lead to a prolongation of the QT/QTc interval above the threshold of regulatory concern.Original Abstract: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT times The largest time-matched difference in QTcI compared with placebo was observed at 1h post dose (mean [90% CI] 7.54 [5.17, 9.90] ms).