Gehin Martine, Sidharta Patricia N, Gnerre Carmela, Treiber Alexander, Halabi Atef, Dingemanse Jasper
Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland,
Eur J Clin Pharmacol. 2015 Jan;71(1):15-23. doi: 10.1007/s00228-014-1767-x. Epub 2014 Oct 18.
Setipiprant, a selective oral CRTH2 antagonist, has been investigated for the treatment of allergic rhinitis and asthma. In vitro data showed that setipiprant has a weak induction potential on CYP3A4. An interaction at the hepatic level between setipiprant and CYP3A4 substrates was not expected even at the dosing regimen of 1,000 mg setipiprant b.i.d. due to the high plasma protein binding. However, at this dosing regimen, interactions at the gut level could not be excluded.
In this single-center, open-label study, 40 mg of simvastatin was administered orally on Day 1, and then concomitantly with setipiprant on Day 10 following 9 days of setipiprant 1,000 mg b.i.d. to 22 healthy male subjects.
In the presence of setipiprant, the simvastatin concentration-time profile was similar to that of simvastatin alone. The concentrations of simvastatin were, however, slightly lower, resulting in a 9 % decrease in C max (geometric mean ratio (GMR) 0.91, 90 % confidence interval (CI) (0.73, 1.13)) and in a 16 % lower AUC0-∞ (GMR 0.84, 90 % CI (0.72, 0.99)). Exposure to simvastatin acid was similar when comparing simvastatin with or without setipiprant. The GMR and 90 % CI for AUC0-∞ were within the 0.8 to 1.25 limits, whereas those for C max were outside (GMR 2.73, 90 % CI (2.11, 3.53)). Moreover, the median t max of simvastatin acid occurred earlier (1.8 h) when combined compared to 3.0 h when administered alone.
As setipiprant has little impact on simvastatin pharmacokinetics, it does not modulate CYP3A4 in a clinically relevant manner.
塞替哌兰特是一种选择性口服CRTH2拮抗剂，已被研究用于治疗过敏性鼻炎和哮喘。体外数据显示，塞替哌兰特对CYP3A4的诱导潜力较弱。由于血浆蛋白结合率高，即使在塞替哌兰特每日两次、每次1000 mg的给药方案下，也预计塞替哌兰特与CYP3A4底物在肝脏水平不会发生相互作用。然而，在该给药方案下，不能排除在肠道水平发生相互作用的可能性。
在这项单中心、开放标签研究中，对22名健康男性受试者在第1天口服40 mg辛伐他汀，然后在第10天，在连续9天每日两次服用1000 mg塞替哌兰特后，与塞替哌兰特同时给药。
在有塞替哌兰特存在的情况下，辛伐他汀的浓度-时间曲线与单独使用辛伐他汀时相似。然而，辛伐他汀的浓度略低，导致Cmax降低9%（几何平均比值（GMR）0.91，90%置信区间（CI）（0.73，1.13）），AUC0-∞降低16%（GMR 0.84，90% CI（0.72，0.99））。比较有或没有塞替哌兰特时的辛伐他汀，其酸的暴露量相似。AUC0-∞的GMR和90% CI在0.8至1.25范围内，而Cmax的GMR和90% CI超出该范围（GMR 2.73，90% CI（2.11，3.53））。此外，联合使用时辛伐他汀酸的中位达峰时间（tmax）较早（1.8小时），而单独给药时为3.0小时。
由于塞替哌兰特对辛伐他汀的药代动力学影响较小，它不会以临床相关方式调节CYP3A4。
