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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >An Open-Label Study to Assess the Effect of Itraconazole and Rifampin on Parsaclisib Pharmacokinetics When Administered Orally in Healthy Participants
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An Open-Label Study to Assess the Effect of Itraconazole and Rifampin on Parsaclisib Pharmacokinetics When Administered Orally in Healthy Participants

机译：在健康参与者口服给药时，评估伊唑唑和利福平对帕萨克斯利斯药代动力学作用的开放式标签研究

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Parsaclisib, a selective, potent phosphatidylinositol 3-kinase delta inhibitor being developed for the treatment of cancer and autoimmune diseases, is primarily metabolized by cytochrome P450 (CYP) 3A4. This study assessed the pharmacokinetics (PK) and safety of parsaclisib alone or combined with itraconazole (potent CYP3A inhibitor) or rifampin (potent CYP3A4 inducer) in healthy participants. In this open-label, fixed-sequence study, cohort 1 received oral parsaclisib 10 mg once daily on days 1 and 8 and oral itraconazole 200 mg once daily on days 4-11; cohort 2 received oral parsaclisib 20 mg once daily on days 1 and 11 and oral rifampin 600 mg once daily on days 4-12. Parsaclisib plasma concentration was tested and PK parameters calculated by noncompartmental analysis.Geometric mean ratios (GMRs) and 2-sided 90% confidence intervals (CIs) were estimated by 2-factor analysis of variance.Thirty-six healthy participants were enrolled (18 per cohort). Parsaclisib maximum plasma drug concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUCq-to) were increased by 21% and 107% with concomitant itraconazole versus parsaclisib alone (GMR, 1.21; 90%CI, 1.14-1.29; and 2.07; 90%CI, 1.97-2.17, respectively). Parsaclisib Cmax and AUC were reduced by 43% and 77%, respectively,with concomitant rifampin versus parsaclisib alone (GMR,0.57;90%CI,0.53-0.60;and 0.23;90%CI,0.2l-0.24,respectively). Headache was the most common adverse event, reported by 13.9% of participants (all in cohort 2). Single-dose parsaclisib alone or combined with itraconazole or rifampin appeared safe and well tolerated in healthy participants. Parsaclisib dose adjustment may be necessary with concomitant administration of strong CYP3A4 inhibitors or inducers.
机译：Parsaclisib是一种选择性、有效的磷脂酰肌醇3-激酶δ抑制剂，用于治疗癌症和自身免疫性疾病，主要由细胞色素P450（CYP）3A4代谢。本研究评估了帕沙利西单独或与伊曲康唑（强效CYP3A抑制剂）或利福平（强效CYP3A4诱导剂）合用在健康受试者中的药代动力学（PK）和安全性。在这项开放标签、固定序列研究中，队列1在第1天和第8天口服帕沙利西10mg，每天一次，在第4-11天口服伊曲康唑200mg；第2组在第1天和第11天口服帕沙利西20mg每日一次，在第4-12天口服利福平600mg每日一次。通过非部分分析测试帕萨科利西的血浆浓度并计算PK参数。几何平均比（GMR）和双侧90%置信区间（CI）通过双因素方差分析进行估计。纳入36名健康参与者（每个队列18名）。帕沙利西最大血浆药物浓度（Cmax）和浓度-时间曲线下面积外推至无穷大（AUCq-to），与单独使用帕沙利西相比，联合使用伊曲康唑增加了21%和107%（GMR，1.21；90%可信区间，1.14-1.29；和2.07；90%可信区间，1.97-2.17）。与单独使用帕沙利西相比，同时使用利福平的帕沙利西Cmax和AUC分别降低43%和77%（GMR，0.57；90%可信区间，0.53-0.60；和0.23；90%可信区间，分别为0.2l-0.24）。头痛是最常见的不良事件，13.9%的参与者（均在队列2中）报告了头痛。在健康参与者中，单剂量帕沙利西或与伊曲康唑或利福平合用似乎安全且耐受性良好。帕萨科利西的剂量调整可能需要同时服用强CYP3A4抑制剂或诱导剂。

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