Eliglustat is an oral glucosylceramide synthase inhibitor indicated for the long-term treatment of adults with Gaucher disease type 1 and CYP2D6 extensive, intermediate, or poor metabolizer phenotypes. Eliglustat is metabolized primarily by CYP2D6 and to a lesser extent by CYP3A4 and is a substrate of P-glycoprotein (P-gp). Three studies evaluated the effects of paroxetine (strong CYP2D6 inhibitor), ketoconazole (strong CYP3A4 and P-gp inhibitor), and rifampin (strong CYP3A4/P-gp inducer; OATP inhibitor) on the pharmacokinetics of orally administered eliglustat in healthy adults. An 8.9-fold increase in eliglustat exposure following co-administration of multiple-dose eliglustat and paroxetine is attributed to inhibition of CYP2D6-mediated metabolism of eliglustat by paroxetine. A 4.3-fold increase in eliglustat exposure following co-administration of multiple-dose eliglustat and ketoconazole is attributed to inhibition of CYP3A4-mediated metabolism and/or P-gp-mediated transport of eliglustat by ketoconazole. Co-administration of eliglustat with oral doses of rifampin reduced eliglustat exposure by >85% due to induction of CYP3A4/P-gp by rifampin, while a single intravenous dose of rifampin had no effect on eliglustat, confirming that eliglustat is not an OATP substrate. Depending on CYP2D6 metabolizer phenotype, co-administration of eliglustat with CYP2D6 and/or CYP3A inhibitors or CYP3A inducers may alter eliglustat exposure, warrant dosage adjustment or use with caution, or be contraindicated.

Eliglustat是一种口服葡萄糖基神经酰胺合酶抑制剂，适用于长期治疗患有Gaucher疾病1型和CYP2D6广泛，中间或不良代谢表型的成年人。Eliglustat主要通过CYP2D6代谢，在较小程度上通过CYP3A4代谢，是P-糖蛋白（P-gp）的底物。三项研究评估了帕罗西汀（强效CYP2D6抑制剂），酮康唑（强效CYP3A4和P-gp抑制剂）和利福平（强效CYP3A4 / P-gp诱导剂; OATP抑制剂）对健康成年人口服eliglustat药代动力学的影响。多剂量eliglustat和paroxetine并用后eliglustat暴露增加8.9倍归因于帕罗西汀抑制CYP2D6介导的eliglustat代谢。A 4。多剂量eliglustat和ketoconazole并用后eliglustat暴露增加3倍是由于酮康唑抑制了CYP3A4介导的代谢和/或P-gp介导的eliglustat转运。由于利福平诱导CYP3A4 / P-gp的作用，依格鲁司他与口服剂量的利福平的共同给药使依格鲁司特的暴露减少> 85％，而单次静脉内剂量的利福平对依格鲁司特没有影响，证实依格鲁司特不是OATP底物。根据CYP2D6代谢物的表型，将eliglustat与CYP2D6和/或CYP3A抑制剂或CYP3A诱导剂合用可能会改变eliglustat的暴露，需要调整剂量或谨慎使用或禁忌。