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Dose titration of BAF 312 attenuates the initial heart rate reducing effect in healthy subjects
Author(s) -
Legangneux Eric,
Gardin Anne,
Johns Donald
Publication year - 2013
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2012.04400.x
Subject(s) - titration , heart rate , medicine , pharmacology , cardiology , chemistry , blood pressure , inorganic chemistry
Aim Previous studies have shown transient decreases in heart rate ( HR ) following administration of sphingosine 1‐phosphate ( S 1 P ) receptor modulators including BAF 312. This study was conducted to determine whether dose titration of BAF 312 reduces or eliminates these effects. Methods Fifty‐six healthy subjects were randomized 1:1:1:1 to receive BAF 312 in one of two dose titration ( DT ) regimens ( DT 1 and DT 2: 0.25–10 mg over 9–10 days), no titration (10 mg starting dose) or placebo. Pharmacodynamic and pharmacokinetic parameters were assessed. Results Neither DT 1 nor DT 2 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 DT 1 and non‐titration was 1.18 (95% confidence interval [ CI ] 1.13, 1.23) and 1.14 (95% CI 1.09, 1.18) for DT 2 (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 DT 1 and DT 2 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. Conclusion Both titration regimens effectively attenuated the initial bradyarrhythmia observed on day 1 of treatment with BAF 312 10 mg.