Authors’ Reply to Srinivas: “Pharmacokinetics and Tolerability of the Novel Oral Prostacyclin IP Receptor Agonist Selexipag”

Abstract

We thank Dr. Srinivas for his interest in our study and for the opportunity to respond to the letter [1]. While we agree with several points, there are others we disagree with.Taking into consideration the much higher potency at the prostacyclin receptor (IP) and the pharmacokinetic characteristics, it is acknowledged that ACT-333679 is the major contributor to the overall efficacy as well as to potential safety relevant effects. Not only is the half-life of selexipag short, but also its exposure is three to four times lower compared with ACT-333679.Dr. Srinivas indicated that the data described in our paper suggested absorption limitation of selexipag at a threshold of 800 lg [1]. However, the single-dose data for both selexipag and ACT-333679 showed a dose-proportional increase in both exposure variables across the dose range tested, from 100 to 800 lg [2]. Gradual up-titration to an individual patient's highest tolerated dose is the generally accepted regimen for IP receptor agonists [3], which has now been extensively studied in healthy subjects up to 1800 lg twice daily (bid) as well as in patients up to 1600 lg bid [4][5][6][7]. The pharmacokinetics of selexipag were dose proportional across the entire dose range following multiple doses, as evidenced by the point estimate of the population mean slope for area under the plasma concentration-time curve during a dose interval (AUC s ) and maximum plasma concentration (C max ) [5]. Also, the pharmacokinetics of the metabolite ACT-333679 were found to be approximately dose proportional.The data following single and multiple doses for selexipag and ACT-333679 clearly illustrate that the pharmacokinetics of selexipag and ACT-333679 are linear. Oral absorption of selexipag in the gastrointestinal tract is not a limiting factor and is not saturated up to a dose of 1800 lg.Regarding the formation of the metabolite, based on nonclinical findings, selexipag undergoes enzymatic hydrolysis by the hepatic carboxylesterase 1 to yield the active metabolite [8]. Thus the metabolite is mainly formed systemically, which is further supported by its delayed appearance in vivo.A small and clinically irrelevant effect of food on the exposure to selexipag was observed in healthy Caucasian subjects. Food had no significant effect on exposure to selexipag and ACT-333679, but it decreased the rate of absorption, as shown by a decrease in C max and a delay in the median time to reach maximum plasma/blood concentration (t max ) of 1-1.5 h. The observed increase in exposure of 10 % for selexipag and decrease of 27 % for ACT-333679 is within the pharmacokinetic variability of the compound, which should also be viewed in the light of the low dose administered, in the microgram range [5,6,8]. Also relevant in this context is that in clinical practice, selexipag is used at an individualized dose of 200-1600 lg bid, reached after weekly up-titration [9]. This means that in clinical practice, selexipag is not administered at a fixed dose; patients are up-titrated to their individual maintenan...