Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.
Department of Thoracic Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
Pharm Res. 2022 Apr;39(4):669-676. doi: 10.1007/s11095-022-03244-8. Epub 2022 Mar 29.
Although kinase inhibitors (KIs) are generally effective, their use has a large impact on the current health care budget. Dosing strategies to reduce treatment costs are warranted. Boosting pharmacokinetic exposure of KIs metabolized by cytochrome P450 (CYP)3A4 with ritonavir might result in lower doses needed and subsequently reduces treatment costs. This study is a proof-of-concept study to evaluate if the dose of erlotinib can be reduced by co-administration with ritonavir.
In this open-label, cross-over study, we compared the pharmacokinetics of monotherapy erlotinib 150 mg once daily (QD) (control arm) with erlotinib 75 mg QD plus ritonavir 200 mg QD (intervention arm). Complete pharmacokinetic profiles at steady-state were taken up to 24 h after erlotinib intake for both dosing strategies.
Nine patients were evaluable in this study. For the control arm, the systemic exposure over 24 h, maximum plasma concentration and minimal plasma concentration of erlotinib were 29.3 μgh/mL (coefficient of variation (CV):58%), 1.84 μg/mL (CV:60%) and 1.00 μg/mL (CV:62%), respectively, compared with 28.9 μgh/mL (CV:116%, p = 0.545), 1.68 μg/mL (CV:68%, p = 0.500) and 1.06 μg/mL (CV:165%, p = 0.150) for the intervention arm. Exposure to the metabolites of erlotinib (OSI-413 and OSI-420) was statistically significant lower following erlotinib plus ritonavir dosing. Similar results regarding safety in both dosing strategies were observed, no grade 3 or higher adverse event was reported.
Pharmacokinetic exposure at a dose of 75 mg erlotinib when combined with the strong CYP3A4 inhibitor ritonavir is similar to 150 mg erlotinib. Ritonavir-boosting is a promising strategy to reduce erlotinib treatment costs and provides a rationale for other expensive therapies metabolized by CYP3A4.
尽管激酶抑制剂（KIs）通常有效，但它们的使用对当前的医疗保健预算有很大影响。需要制定降低治疗成本的剂量策略。用利托那韦增强细胞色素 P450（CYP）3A4 代谢的 KI 的药代动力学暴露可能会导致所需剂量降低，从而降低治疗成本。这项研究是一项概念验证研究，旨在评估厄洛替尼与利托那韦联合使用是否可以减少剂量。
在这项开放标签、交叉研究中，我们比较了单药厄洛替尼 150mg 每日一次（QD）（对照组）与厄洛替尼 75mg QD 加利托那韦 200mg QD（干预组）的药代动力学。两种给药方案均在厄洛替尼摄入后 24 小时内采集稳态时的完整药代动力学曲线。
这项研究中共有 9 名患者可评估。对于对照组，厄洛替尼的 24 小时系统暴露量、最大血浆浓度和最小血浆浓度分别为 29.3μgh/mL（变异系数（CV）：58%）、1.84μg/mL（CV：60%）和 1.00μg/mL（CV：62%），而干预组分别为 28.9μgh/mL（CV：116%，p=0.545）、1.68μg/mL（CV：68%，p=0.500）和 1.06μg/mL（CV：165%，p=0.150）。厄洛替尼加用利托那韦后，厄洛替尼代谢物（OSI-413 和 OSI-420）的暴露量有统计学意义降低。两种给药方案的安全性结果相似，均未报告 3 级或更高级别的不良事件。
当与强 CYP3A4 抑制剂利托那韦联合使用时，厄洛替尼的 75mg 剂量的药代动力学暴露与 150mg 厄洛替尼相似。利托那韦增强是降低厄洛替尼治疗成本的有前途的策略，并为其他由 CYP3A4 代谢的昂贵疗法提供了依据。
