Abstract
Ponesimod, a selective S1P1 receptor modulator, reduces the blood lymphocyte count in all tested species by preventing egress of T and B cells from thymus and peripheral lymphoid organs. In addition, ponesimod transiently affects heart rate and atrioventricular (AV) conduction in humans, effects not observed in mice, rats, and dogs with selective S1P1 receptor modulators, suggesting that the regulation of heart rate and rhythm is species dependent. In the present study, we used conscious guinea pigs implanted with a telemetry device to investigate the effects of single and multiple oral doses of ponesimod on ECG variables, heart rate, and blood pressure. Oral administration of ponesimod did not affect the sinus rate (P rate) but dose-dependently induced AV block type I to III. A single oral dose of 0.1 mg/kg had no effect on ECG variables, while a dose of 3 mg/kg induced AV block type III in all treated guinea pigs. Repeated oral dosing of 1 or 3 mg/kg ponesimod resulted in rapid desensitization, so that the second dose had no or a clearly reduced effect on ECG variables as compared with the first dose. Resensitization of the S1P1 receptor in the heart was concentration dependent. After desensitization had been induced by the first dose of ponesimod, the cardiac system remained desensitized as long as the plasma concentration was ≥75 ng/ml. By using a progressive up-titration regimen, the first-dose effect of ponesimod on heart rate and AV conduction was significantly reduced due to desensitization of the S1P1 receptor. In summary, conscious guinea pigs implanted with a telemetry device represent a useful model to study first-dose effects of S1P1 receptor modulators on heart rate and rhythm. This knowledge was translated to a dosing regimen of ponesimod to be tested in humans to avoid or significantly reduce the first-dose effects.
Highlights
Ponesimod is a selective sphingosine 1-phosphate receptor 1 (S1P1) modulator under investigation for the treatment of multiple sclerosis and psoriasis [1,2]
Sphingosine 1-phosphate (S1P) and the S1P1 receptor are essential for lymphocyte trafficking and regulate egress of T and B cells from thymus and peripheral lymphoid organs [5,6]
S1P and the S1P1 receptor are essential for lymphocyte trafficking in all species studied and regulate egress of T and B cells from thymus and peripheral lymphoid organs [5,6]
Summary
Ponesimod is a selective sphingosine 1-phosphate receptor 1 (S1P1) modulator under investigation for the treatment of multiple sclerosis and psoriasis [1,2]. Sphingosine 1-phosphate (S1P), a lipid mediator derived from membrane sphingolipids, is involved in a myriad of physiological processes throughout the body, including the immune, cardiovascular, and central nervous systems [3,4]. The effects of extracellular S1P are mediated by five G proteincoupled receptors (GPCR), S1P1 to S1P5, which exhibit different patterns of tissue expression and are linked to diverse physiological responses [4]. The first drug in this class, the non-selective S1P receptor modulator fingolimod, was approved in 2010 for the treatment of patients with relapsing multiple sclerosis
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