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Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects

Legangneux, Eric, Gardin, Anne and Johns, Donald (2012) Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects. British Journal of Clinical Pharmacology, 10 (1111). pp. 1365-2125. ISSN 0306-5251


BAF312 is the next generation selective sphingosine 1-phosphate receptor modulator (S1PR) that targets multiple sclerosis via effects on the immune system, and may have direct effects on S1PR-expressing cells in the central nervous system. Previous studies have shown transient decreases in heart rate (HR) following administration of S1PR modulators including BAF312. The objective of the current study is to determine whether dose titration of BAF312 reduces or eliminates these effects.
56 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 treatment difference on each of Days 1–12 vs. the non-titration regimen on Day 1 for HR effects (P < 0.0001). HRs in the non-titration regimen 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 bpm; P ≤ 0.0001). By Day 9, HRs in both titration regimens were comparable to placebo; this effect was maintained until end of treatment Day 12.
Both titration regimens effectively attenuated the initial bradyarrhythmia observed on Day 1 of treatment with BAF312 10 mg.

Item Type: Article
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Keywords: BAF312, heart rate
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14


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