Contributions
Abstract: P796
Type: Poster
Abstract Category: Therapy - disease modifying - 32 Others
Background: Siponimod, a modulator of sphingosine 1-phosphate receptor subtypes 1 and 5 (S1P1,5) is primarily metabolised in the liver by CYP2C9 and CYP3A4. Rifampin is one of the most potent inducers of CYP2C9/3A4 enzymes. This study evaluated the effect of a simultaneous induction of both metabolising enzymes on siponimod pharmacokinetics (PK) to support the development of clinical recommendations for siponimod co-administration with CYP2C9/3A4 inducers.
Objective: To investigate the PK, safety and tolerability of multiple doses of siponimod 2mg qd and its selected metabolites (M3 and M5) when administered with or without rifampin in healthy subjects.
Methods: This was a confirmatory, open-label, multiple-dose, two-period study in healthy subjects aged 18-45 years. In Period 1 (Days 1-12), siponimod alone was administered orally in multiple doses, up titrated from 0.25 to 2mg over 6 days and 2mg qd from Days 6-12. In Period 2 (Days 13-24), siponimod 2mg qd was co-administered with rifampin 600mg qd. Primary assessments included PK of siponimod (Days 12 and 24; Cmax,ss, Tmax,ss, AUCtau,ss). Data are presented as geometric mean, except Tmax as median (range). Key secondary assessments included PK of M3 (glucuronidation) and M5 (hydroxylation) metabolites and safety/tolerability of siponimod. Change in absolute lymphocyte count (ALC) was also measured.
Results: Of the 16 subjects enrolled, 15 completed the study. Mean±SD age was 31±8.3 years; 94% were men. When siponimod was administered alone, Cmax,ss of 28.6 ng/mL was achieved in 4h (Tmax,ss range 1.5-8) and AUCtau,ss was 546 h*ng/mL. When co-administered with rifampin, Cmax,ss and AUCtau,ss decreased to 15.7 ng/mL and 235 h*ng/mL, respectively. Tmax remained the same (4h). In the presence of rifampin, Cmax,ss of M3 increased (53%), while AUCtau,ss showed minor change; the Cmax,ss of M5 remained the same, while AUCtau,ss decreased (37%). Siponimod mean trough levels in Period 2 suggest the maximum induction conditions by Day 24. No severe or serious adverse events (AEs) were reported. Higher incidence of AEs was reported in Period 2 (86.7%) vs Period 1 (50%). Mean ALC slightly increased in rifampin's presence but remained below 1.0×109/L.
Conclusions: Siponimod Cmax,ss and AUCtau,ss decreased by 45% and 57%, respectively, in rifampin's presence. Despite significant reduction in siponimod exposure, rifampin or any other potent CYP2C9/3A4 inducer can be co-administered with siponimod for a short period (up to 1 month).
Disclosure:
Funding source: This study was funded by Novartis Pharma AG.
Antonia M. Davidson is a Principal Investigator at the PPD Phase 1 Clinic, Austin, TX, USA.
Anne Gardin, Cathy Gray, Srikanth Neelakantham, Felix Huth, Swati Dumitras, Eric Legangneux and Kasra Shakeri-Nejad are employees of Novartis.
Abstract: P796
Type: Poster
Abstract Category: Therapy - disease modifying - 32 Others
Background: Siponimod, a modulator of sphingosine 1-phosphate receptor subtypes 1 and 5 (S1P1,5) is primarily metabolised in the liver by CYP2C9 and CYP3A4. Rifampin is one of the most potent inducers of CYP2C9/3A4 enzymes. This study evaluated the effect of a simultaneous induction of both metabolising enzymes on siponimod pharmacokinetics (PK) to support the development of clinical recommendations for siponimod co-administration with CYP2C9/3A4 inducers.
Objective: To investigate the PK, safety and tolerability of multiple doses of siponimod 2mg qd and its selected metabolites (M3 and M5) when administered with or without rifampin in healthy subjects.
Methods: This was a confirmatory, open-label, multiple-dose, two-period study in healthy subjects aged 18-45 years. In Period 1 (Days 1-12), siponimod alone was administered orally in multiple doses, up titrated from 0.25 to 2mg over 6 days and 2mg qd from Days 6-12. In Period 2 (Days 13-24), siponimod 2mg qd was co-administered with rifampin 600mg qd. Primary assessments included PK of siponimod (Days 12 and 24; Cmax,ss, Tmax,ss, AUCtau,ss). Data are presented as geometric mean, except Tmax as median (range). Key secondary assessments included PK of M3 (glucuronidation) and M5 (hydroxylation) metabolites and safety/tolerability of siponimod. Change in absolute lymphocyte count (ALC) was also measured.
Results: Of the 16 subjects enrolled, 15 completed the study. Mean±SD age was 31±8.3 years; 94% were men. When siponimod was administered alone, Cmax,ss of 28.6 ng/mL was achieved in 4h (Tmax,ss range 1.5-8) and AUCtau,ss was 546 h*ng/mL. When co-administered with rifampin, Cmax,ss and AUCtau,ss decreased to 15.7 ng/mL and 235 h*ng/mL, respectively. Tmax remained the same (4h). In the presence of rifampin, Cmax,ss of M3 increased (53%), while AUCtau,ss showed minor change; the Cmax,ss of M5 remained the same, while AUCtau,ss decreased (37%). Siponimod mean trough levels in Period 2 suggest the maximum induction conditions by Day 24. No severe or serious adverse events (AEs) were reported. Higher incidence of AEs was reported in Period 2 (86.7%) vs Period 1 (50%). Mean ALC slightly increased in rifampin's presence but remained below 1.0×109/L.
Conclusions: Siponimod Cmax,ss and AUCtau,ss decreased by 45% and 57%, respectively, in rifampin's presence. Despite significant reduction in siponimod exposure, rifampin or any other potent CYP2C9/3A4 inducer can be co-administered with siponimod for a short period (up to 1 month).
Disclosure:
Funding source: This study was funded by Novartis Pharma AG.
Antonia M. Davidson is a Principal Investigator at the PPD Phase 1 Clinic, Austin, TX, USA.
Anne Gardin, Cathy Gray, Srikanth Neelakantham, Felix Huth, Swati Dumitras, Eric Legangneux and Kasra Shakeri-Nejad are employees of Novartis.