Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects
Article first published online: 5 FEB 2013
© 2012 Novartis Institutes for BioMedical Research (NIBIR). British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Special Issue: Nutraceuticals Themed Section
Volume 75, Issue 3, pages 831–841, March 2013
How to Cite
Legangneux, E., Gardin, A. and Johns, D. (2013), Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects. British Journal of Clinical Pharmacology, 75: 831–841. doi: 10.1111/j.1365-2125.2012.04400.x
- Issue published online: 5 FEB 2013
- Article first published online: 5 FEB 2013
- Accepted manuscript online: 30 JUL 2012 09:55PM EST
- Manuscript Accepted: 24 JUL 2012
- Manuscript Received: 20 JAN 2012
- Novartis Pharma AG, Basel, Switzerland
- dose-response relationship;
- heart rate;
- phase I as topic;
- sphingosine/analogues and derivatives
Previous studies have shown transient decreases in heart rate (HR) following administration of sphingosine 1-phosphate (S1P) receptor modulators including BAF312. This study was conducted to determine whether dose titration of BAF312 reduces or eliminates these effects.
Fifty-six healthy subjects were randomized 1:1:1:1 to receive BAF312 in one of two dose titration (DT) regimens (DT1 and DT2: 0.25–10 mg over 9–10 days), no titration (10 mg starting dose) or placebo. Pharmacodynamic and pharmacokinetic parameters were assessed.
Neither DT1 nor DT2 resulted in clinically significant bradycardia or atrioventricular conduction effects. Both titration regimens showed a favourable difference on each of days 1–12 vs. the non-titration regimen on day 1 for HR effects (P < 0.0001). On day 1, the geometric mean ratio of the fraction from the previous day in minimum daily HR between DT1 and non-titration was 1.18 (95% confidence interval [CI] 1.13, 1.23) and 1.14 (95% CI 1.09, 1.18) for DT2 (both P < 0.05) with significant differences noted through to day 12. Non-titration HRs showed considerable separation from placebo throughout the study. There was no statistically significant reduction in HR vs. placebo on day 1 in either titration regimen. On days 3–7 subjects in DT1 and DT2 experienced minor reductions in HR vs. placebo (approximately 5 beats min−1; P ≤ 0.0001). From days 9–12, HRs in both titration regimens were comparable with placebo.
Both titration regimens effectively attenuated the initial bradyarrhythmia observed on day 1 of treatment with BAF312 10 mg.