Dose Justification for Asciminib in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia with and Without the T315I Mutation,Clinical Pharmacokinetics

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Dose Justification for Asciminib in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia with and Without the T315I Mutation
Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2024-09-07 , DOI: 10.1007/s40262-024-01411-1
Francois Pierre Combes ₁ , Sherwin K B Sy ₁ , Ying Fei Li ₁ , Sebastien Lorenzo ₂ , Kohinoor Dasgupta ₃ , Shruti Kapoor ₁ , Matthias Hoch ₄ , Yu-Yun Ho ₁

Affiliation

Background and Objective

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.

Methods

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.

Results

PopPK showed comparable exposure (area under the curve, AUC_0-24h) 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.

Conclusions

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.

中文翻译：

Asciminib 在有和没有 T315I 突变的费城染色体阳性慢性粒细胞白血病患者中的剂量合理性

背景和目标

Asciminib 被批准用于慢性期费城染色体阳性慢性粒细胞白血病（Ph+ CML-CP）患者，≥ 2 种既往酪氨酸激酶抑制剂治疗。在这里，我们旨在证明 asciminib 80 mg 每日一次（q.d.）与 40 mg 每日两次（b.i.d.）在没有 T315I 突变的 CML-CP 患者中的疗效/安全性相似性，并支持在携带 T315I 的患者中使用 200 mg b.i.d. 剂量，使用模型知情药物开发。

方法

从 I 期研究的 199 名患者（NCT02081378;10-200 mg b.i.d. 或 10-400 mg q.d.）和 III 期研究的 154 名患者（NCT03106779;40 mg b.i.d.）中收集数据。评估基于群体药代动力学（PopPK）和暴露-反应（疗效/安全性）分析。

结果

PopPK 显示 40 mg b.i.d. 和 80 mg q.d. 的暴露量相当（曲线下面积，AUC_0-24h）（12,638 vs 12,646 ng*h/mL）;80 mg q.d. 的平均最大和最低血浆浓度分别为 40 mg b.i.d. 的 1.61 倍和 0.72 倍。暴露-反应分析预测 40 mg b.i.d. 和 80 mg q.d. 的主要分子反应率相似（第 24 周：27.6% 对 24.8%;第 48 周：32.3% 对 30.6%）。结果还确定了 T315I 突变患者 200 mg b.i.d. 的充分性（第 24 周：20.7%;第 48 周：23.7%），以及所有剂量方案的相似安全性。