Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, New Jersey, USA.
Certara Strategic Consulting, Montreal, Canada.
J Clin Pharmacol. 2020 Aug;60(8):1061-1075. doi: 10.1002/jcph.1602. Epub 2020 Mar 13.
Multiple myeloma is an incurable progressive neoplastic disease that accounts for 10% of all hematologic malignancies. Even though significant progress has been made in the treatment of newly diagnosed multiple myeloma, the disease follows a relapsing course in the majority of patients, and there is a need for more effective therapeutic options for the treatment of relapsed or refractory multiple myeloma. CC-4047-MM-005 and CC-4047-MM-007 were phase 1 and 3 studies to evaluate the novel combination of pomalidomide, bortezomib, and low-dose dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have already received lenalidomide-based treatments early. This analysis was performed to characterize the population pharmacokinetics (PK) of pomalidomide from the combination treatment and to examine exposure-response relationships. Our analysis showed that pomalidomide concentration-time profiles from the combination treatment were adequately described with a 1-compartment PK model, with first-order absorption and elimination and pomalidomide exhibiting linear and time-invariant PK with moderate variability from the combination treatment. Except for the body surface area, none of the tested covariates had an effect on pomalidomide PK. Although body surface area was identified as a statistically significant covariate of pomalidomide PK, the impact was not deemed clinically relevant. A flat exposure-response curve was observed, consistent with a near-saturated drug effect at the tested exposure range suggesting an appropriately recommended clinical dose of 4 mg of pomalidomide for the combination treatment. Finally, pomalidomide exposure was not associated with higher probabilities of dose interruption during cycle 1 or dose reduction during the treatment period.
多发性骨髓瘤是一种无法治愈的进行性肿瘤性疾病，占所有血液系统恶性肿瘤的 10%。尽管新诊断多发性骨髓瘤的治疗取得了重大进展，但大多数患者的疾病仍呈复发过程，需要更有效的治疗选择来治疗复发或难治性多发性骨髓瘤。CC-4047-MM-005 和 CC-4047-MM-007 是评估泊马度胺、硼替佐米和低剂量地塞米松联合治疗已接受来那度胺为基础治疗的复发或难治性多发性骨髓瘤患者的 1 期和 3 期研究。进行这项分析是为了描述联合治疗中泊马度胺的群体药代动力学（PK），并考察暴露-反应关系。我们的分析表明，联合治疗中泊马度胺的浓度-时间曲线可以用 1 室 PK 模型充分描述，具有一级吸收和消除，泊马度胺表现出线性和时间不变的 PK，与联合治疗的中度变异性。除了体表面积外，没有测试的协变量对泊马度胺 PK 有影响。虽然体表面积被确定为泊马度胺 PK 的统计学显著协变量，但影响被认为无临床意义。观察到暴露-反应曲线平坦，与测试暴露范围内接近饱和的药物效应一致，表明联合治疗中推荐的 4mg 泊马度胺临床剂量适当。最后，泊马度胺的暴露与第 1 周期中断剂量或治疗期间降低剂量的可能性增加无关。
