Margaux Boehler1, Pierre-Eric Juif2, Matthias Hoch1, Jasper Dingemanse1. 1. Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland. 2. Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland. pierre-eric.juif@actelion.com.
Abstract
BACKGROUND AND OBJECTIVES: The pharmacokinetic profile of ponesimod, a sphingosine-1-phosphate receptor 1 modulator, is characterized by a rapid absorption [time to maximum concentration (t max) of 2-4 h] and a terminal half-life (t ½) of 32 h after single-dose administration. The aim of this study was to assess additional pharmacokinetic parameters [absolute bioavailability, total clearance (CL), and volume of distribution (V ss)] in healthy male subjects. METHODS: After ensuring in a pilot phase the full pharmacokinetic profile, safety, and tolerability of a 5-mg intravenous infusion of ponesimod over 3 h (treatment A), the study proceeded to the randomized, two-way crossover, single-dose (treatment A; treatment B: 10 mg oral) main phase. RESULTS: The absolute bioavailability of ponesimod was 83.8 % [90 % confidence interval (CI): 80.2-87.5]. CL and V ss (95 % CI) were 3.8 L/h (3.3-4.3) and 160 L (146.1-174.2), respectively. C max (95 % CI) was 48.5 ng/mL (43.9-53.6) and 61.4 ng/mL (55.3-68.3) after intravenous infusion and oral administration, respectively. The t ½ (95 % CI) following intravenous infusion was 32.9 h (28.5-38.1) and 31.7 h (27.9-36.0) following oral administration. Ponesimod administered by both routes of administration was well tolerated and resulted in transient decreases in lymphocyte count and heart rate. CONCLUSIONS: This study indicates high absolute bioavailability, low CL, and moderate V ss of ponesimod.
RCT Entities:
BACKGROUND AND OBJECTIVES: The pharmacokinetic profile of ponesimod, a sphingosine-1-phosphate receptor 1 modulator, is characterized by a rapid absorption [time to maximum concentration (t max) of 2-4 h] and a terminal half-life (t ½) of 32 h after single-dose administration. The aim of this study was to assess additional pharmacokinetic parameters [absolute bioavailability, total clearance (CL), and volume of distribution (V ss)] in healthy male subjects. METHODS: After ensuring in a pilot phase the full pharmacokinetic profile, safety, and tolerability of a 5-mg intravenous infusion of ponesimod over 3 h (treatment A), the study proceeded to the randomized, two-way crossover, single-dose (treatment A; treatment B: 10 mg oral) main phase. RESULTS: The absolute bioavailability of ponesimod was 83.8 % [90 % confidence interval (CI): 80.2-87.5]. CL and V ss (95 % CI) were 3.8 L/h (3.3-4.3) and 160 L (146.1-174.2), respectively. C max (95 % CI) was 48.5 ng/mL (43.9-53.6) and 61.4 ng/mL (55.3-68.3) after intravenous infusion and oral administration, respectively. The t ½ (95 % CI) following intravenous infusion was 32.9 h (28.5-38.1) and 31.7 h (27.9-36.0) following oral administration. Ponesimod administered by both routes of administration was well tolerated and resulted in transient decreases in lymphocyte count and heart rate. CONCLUSIONS: This study indicates high absolute bioavailability, low CL, and moderate V ss of ponesimod.
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