背景:间变性淋巴瘤激酶(ALK)基因的改变在间变性大细胞淋巴瘤(ALCL)的发病机制中起关键作用。克唑替尼是ALK的小分子竞争性抑制剂,ROS1和MET激酶被批准用于ALK阳性复发或难治性儿科患者,系统性ALCL,ALK阳性不能切除,经常性,或难治性炎性肌纤维母细胞瘤(IMT)。
方法:来自复发性或难治性实体瘤患儿的Crizotinib数据,IMT,或ALCL纳入分析.所有患者均以每天两次(BID)100至365mg/m2的剂量口服克唑替尼。进行PopPK分析以表征儿科患者的克唑替尼处置。进行暴露-反应(ER)安全性和抗肿瘤分析以表征克唑替尼剂量或暴露与安全性和感兴趣的抗肿瘤活性终点之间的关系。
结果:群体药代动力学(popPK),ER安全,ER抗肿瘤分析包括98、110和36名儿科患者,分别。具有异速尺度的单室药代动力学模型,一阶消除,具有滞后时间的一阶吸收充分描述了数据。自然对数转换模型预测的克唑替尼AUCss(浓度-时间曲线下的稳态面积)显示出显著的,与≥3级中性粒细胞减少和任何级别视觉障碍呈正相关。克唑替尼剂量与客观缓解率呈正相关。
结论:在不同年龄或不同类型的肿瘤中,PK没有显著差异。建议基于体表面积(BSA)的剂量根据患者体型差异进行适当调整,以在幼儿和青少年儿科患者中实现相似的全身克唑替尼暴露.除≥3级中性粒细胞外,无骨髓抑制事件与克唑替尼剂量或暴露量有显著关系,提示对于ALK突变的儿科癌症患者,克唑替尼是一种可耐受的治疗方案,与传统化疗方案相比,其血液学毒性较小.所呈现的分析结果支持产品标签中的儿科给药建议。
BACKGROUND: Alterations in the ALK (anaplastic lymphoma kinase) gene play a critical role in pathogenesis of anaplastic large cell lymphoma (ALCL).
Crizotinib is a small molecule competitive inhibitor of ALK, ROS1, and MET kinases and was approved for pediatric patients with ALK-positive relapsed or refractory, systemic ALCL, and ALK-positive unresectable, recurrent, or refractory inflammatory myofibroblastic tumors (IMT).
METHODS: Crizotinib data from pediatric patients with relapsed or refractory solid tumors, IMT, or ALCL were included in the analyses. All patients received
crizotinib orally at doses ranging from 100 to 365 mg/m2 twice daily (BID). PopPK analyses were conducted to characterize
crizotinib disposition in pediatric patients. Exposure-response (ER) safety and antitumor analyses were conducted to characterize relationships between crizotinib dose or exposure with safety and antitumor activity endpoints of interest.
RESULTS: The population pharmacokinetic (popPK), ER safety, and ER antitumor analysis included 98, 110, and 36 pediatric patients, respectively. A one-compartment pharmacokinetic model with allometric scaling, first-order elimination, and first-order absorption with lag time adequately described the data. Natural log-transformed model-predicted crizotinib AUCss (steady-state area under the concentration-time curve) demonstrated a significant, positive relationship with Grade ≥3 NEUTROPENIA and Any Grade VISION DISORDER.
Crizotinib dose demonstrated a positive relationship with objective response rate.
CONCLUSIONS: No significant differences in PK were identified across a wide range of ages or across tumor types, suggesting body surface area (BSA)-based dosing adequately adjusted for differences in patient size to achieve similar systemic crizotinib exposures across young children and adolescent pediatric patients. None of the myelosuppressive events except Grade ≥3 NEUTROPENIA had significant relationships identified with crizotinib dose or exposure, suggesting crizotinib is a tolerable treatment with less hematological toxicity than traditional chemotherapy regimens for pediatric patients with ALK-mutated cancers. Results from the presented analyses support the pediatric dosing recommendations in the product label.