Oncology Clinical Pharmacology, Novartis Pharma AG, 4002, Basel, Switzerland.
PAREXEL International, Durham, NC, USA.
Cancer Chemother Pharmacol. 2018 Nov;82(5):847-855. doi: 10.1007/s00280-018-3677-6. Epub 2018 Aug 31.
Eltrombopag is indicated in patients with severe aplastic anemia (SAA) refractory to prior immunosuppressive therapy. The combination of eltrombopag and immunosuppressive therapy (such as cyclosporine) is currently being evaluated in patients with treatment-naive SAA. Cyclosporine is a human breast cancer resistance protein (BCRP) inhibitor, and can potentially alter plasma exposure to eltrombopag, a BCRP substrate. This phase 1, open-label, randomized, 3-period, crossover study evaluated the effect of cyclosporine on the pharmacokinetics of eltrombopag in healthy adults.
Thirty-nine subjects were randomized to either single dose of eltrombopag 50 mg, cyclosporine 200 mg + eltrombopag 50 mg or cyclosporine 600 mg + eltrombopag 50 mg treatment groups. Eltrombopag pharmacokinetic parameters (C, t, AUC, AUC, %AUC, t, and CL/F) were determined using noncompartmental methods.
Geometric mean AUC, AUC, and C, were decreased by 18, 20, and 25%, respectively, for cyclosporine 200 mg + eltrombopag and by 24, 22, and 39%, respectively, for cyclosporine 600 mg + eltrombopag groups compared to the eltrombopag alone group. The median t was prolonged by ~ 1 h in both coadministration treatments. The geometric mean t was ≈ 21, ≈ 24, and ≈ 26 h, respectively, in cyclosporine 200 mg + eltrombopag, cyclosporine 600 mg + eltrombopag and eltrombopag alone groups. All the treatments were safe and well-tolerated. No serious adverse event or death was reported during the study.
These changes in exposure were not considered clinically meaningful as the dose of eltrombopag is adjusted using within-patient dose titration based on platelet counts.
依鲁替尼适用于对先前免疫抑制治疗无效的严重再生障碍性贫血（SAA）患者。依鲁替尼联合免疫抑制治疗（如环孢素）目前正在治疗初治 SAA 患者中进行评估。环孢素是一种人乳腺癌耐药蛋白（BCRP）抑制剂，可能会改变 BCRP 底物依鲁替尼的血浆暴露。这项 1 期、开放标签、随机、3 期、交叉研究评估了环孢素对健康成年人中依鲁替尼药代动力学的影响。
39 名受试者被随机分为单剂量依鲁替尼 50mg、环孢素 200mg+依鲁替尼 50mg 或环孢素 600mg+依鲁替尼 50mg 治疗组。采用非房室法测定依鲁替尼的药代动力学参数（C、t、AUC、AUC、%AUC、t 和 CL/F）。
与依鲁替尼单药组相比，环孢素 200mg+依鲁替尼组的 AUC、AUC 和 C 的几何均数分别降低了 18%、20%和 25%，环孢素 600mg+依鲁替尼组的 AUC、AUC 和 C 的几何均数分别降低了 24%、22%和 39%。两种联合用药治疗组的中位 t 延长约 1h。在环孢素 200mg+依鲁替尼组、环孢素 600mg+依鲁替尼组和依鲁替尼单药组中，几何均数 t 分别约为 21h、24h 和 26h。所有治疗均安全且耐受良好。研究期间未报告严重不良事件或死亡。
由于依鲁替尼的剂量根据血小板计数进行患者内剂量滴定调整，因此这些暴露量的变化不被认为具有临床意义。
