Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA.
Janssen Research & Development, LLC, Spring House, PA, USA.
Cancer Chemother Pharmacol. 2018 Aug;82(2):299-308. doi: 10.1007/s00280-018-3613-9. Epub 2018 Jun 7.
This drug-interaction study evaluated the effect of omeprazole, a proton-pump inhibitor, on ibrutinib's pharmacokinetics (PK) in healthy participants.
This open-label, sequential-design study included 20 healthy adults aged 18-55 years. Ibrutinib (560 mg, single dose) was administered after an overnight fast alone on day 1 and with omeprazole on day 7. Omeprazole (40 mg) alone was administered on days 3-6, 1 h before breakfast; and after an overnight fast on day 7, followed by ibrutinib 2 h later. Blood was sampled on days 1 and 7 for up to 48 h postdose, and the standard PK parameters for ibrutinib and PCI-45227 were summarized using descriptive statistics. The effect of omeprazole on ibrutinib's PK was determined by assessing geometric mean ratios (GMRs) and 90% CIs. Mechanistic modeling was performed using the BTK-receptor occupancy (RO) model.
AUC and AUC of ibrutinib plus omeprazole versus ibrutinib alone showed a modest decrease (GMR [90% CI] 98.3% [83.1-116.3] and 92.5% [77.8-109.9], respectively); C decreased by 62.5% (GMR [90% CI] 37.5% [26.4-53.4]), with delayed t (1-2 h) and terminal half-life unaffected. Mean AUC for PCI-45227 (primary metabolite) was ~ 20% lower with ibrutinib plus omeprazole versus ibrutinib alone. Model predictions showed no impact of decreased C on BTK target engagement. No new safety signals were identified with the use of ibrutinib in this study.
The decrease in C without a corresponding decrease in AUC by omeprazole was not clinically relevant for ibrutinib's bioavailability. No dose adjustments are recommended during ibrutinib's co-administration with omeprazole or other pH-altering agents.
这项药物相互作用研究评估了质子泵抑制剂奥美拉唑对健康参与者中伊布替尼药代动力学（PK）的影响。
这是一项开放标签、序贯设计的研究，纳入了 20 名年龄在 18-55 岁之间的健康成年人。伊布替尼（560mg，单次剂量）在禁食过夜后于第 1 天单独给药，第 7 天与奥美拉唑联合给药。奥美拉唑（40mg）于第 3-6 天单独给药，在早餐前 1 小时；第 7 天禁食过夜后，2 小时后给予伊布替尼。在给药后 48 小时内采集第 1 天和第 7 天的血样，并使用描述性统计方法总结伊布替尼和 PCI-45227 的标准 PK 参数。通过评估几何平均比（GMR）和 90%置信区间（CI）来确定奥美拉唑对伊布替尼 PK 的影响。使用 BTK 受体占有率（RO）模型进行机制建模。
与伊布替尼单药相比，伊布替尼加奥美拉唑的 AUC 和 AUC 略有下降（GMR [90%CI] 98.3%[83.1-116.3]和 92.5%[77.8-109.9]）；C 降低了 62.5%（GMR [90%CI] 37.5%[26.4-53.4]），t （1-2h）和终末半衰期无变化。与伊布替尼单药相比，伊布替尼加奥美拉唑时主要代谢物 PCI-45227 的 AUC 降低约 20%。模型预测显示，C 的降低对 BTK 靶标占有率没有影响。在这项研究中，伊布替尼的使用未发现新的安全性信号。
奥美拉唑对伊布替尼生物利用度的影响无临床意义，即 C 的降低而 AUC 无相应降低。在伊布替尼与奥美拉唑或其他 pH 调节剂联合使用时，无需调整剂量。
