阿西米尼（Asciminib）被批准用于治疗已接受≥2种酪氨酸激酶抑制剂治疗的费城染色体阳性慢性粒细胞白血病慢性期（Ph CML-CP）患者。在这里，我们的目的是证明阿西米尼 80 毫克每日一次（q.d.）与 40 毫克每日两次（b.i.d.）对于无 T315I 突变的 CML-CP 患者的疗效/安全性相似，并支持使用 200 毫克每日两次（b.i.d.）。使用基于模型的药物开发，确定携带 T315I 的患者的剂量。数据收集自 199 名 I 期患者（NCT02081378；10-200 mg b.i.d. 或 10-400 mg q.d.）和 154 名 III 期患者（NCT03106779；40 mg）。 b.i.d.）研究。评估基于群体药代动力学 (PopPK) 和暴露反应（功效/安全性）分析。PopPK 显示每日 40 毫克的暴露量（曲线下面积，AUC0-24 小时）相当。和 80 毫克，每日一次（12,638 与 12,646 ng*h/mL）；每日 80 毫克的平均最大和最小血浆浓度分别是 40 mg b.i.d. 的 1.61 倍和 0.72 倍。暴露反应分析预测 40 毫克每日两次的主要分子反应率相似。和 80 毫克，每日一次（第 24 周：27.6% vs 24.8%；第 48 周：32.3% vs 30.6%）。结果还确定了 200 毫克每日两次的充足性。在 T315I 突变患者中（第 24 周：20.7%；第 48 周：23.7%），所有剂量方案的安全性相似。 40 mg b.i.d. 之间的相似性和 80 毫克，每日一次对这些治疗方案进行了研究，结果表明，在没有 T315I 突变的患者中，具有相似且显着的疗效和良好的耐受性安全性。 200 毫克每日两次该剂量被认为对 T315I 突变患者安全有效。© 2024。作者。

Asciminib is approved in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) treated with ≥ 2 prior tyrosine kinase inhibitors. Here, we aimed to demonstrate similarity in efficacy/safety of asciminib 80 mg once daily (q.d.) versus 40 mg twice daily (b.i.d.) in patients with CML-CP without T315I mutation and support the use of the 200-mg b.i.d. dosage in patients harboring T315I, using model-informed drug development.Data were collected from 199 patients in the phase I (NCT02081378; 10-200 mg b.i.d. or 10-400 mg q.d.) and 154 patients in the phase III (NCT03106779; 40 mg b.i.d.) studies. Evaluations were based on population pharmacokinetics (PopPK) and exposure-response (efficacy/safety) analyses.PopPK showed comparable exposure (area under the curve, AUC0-24h) for 40 mg b.i.d. and 80 mg q.d. (12,638 vs 12,646 ng*h/mL); average maximum and minimum plasma concentrations for 80 mg q.d. were 1.61- and 0.72-fold those of 40 mg b.i.d., respectively. Exposure-response analyses predicted similar major molecular response rates for 40 mg b.i.d. and 80 mg q.d. (Week 24: 27.6% vs 24.8%; Week 48: 32.3% vs 30.6%). Results also established adequacy of 200 mg b.i.d. in patients with T315I mutation (Week 24: 20.7%; Week 48: 23.7%), along with a similar safety profile for all dose regimens.Similarity between 40 mg b.i.d. and 80 mg q.d. regimens was investigated, demonstrating similar and substantial efficacy with well-tolerated safety in patients without T315I mutation. The 200-mg b.i.d. dose was deemed safe and effective for patients with T315I mutation.© 2024. The Author(s).