Pfizer Inc., San Diego, California, USA.
CPT Pharmacometrics Syst Pharmacol. 2023 Nov;12(11):1619-1625. doi: 10.1002/psp4.12882. Epub 2022 Nov 16.
The optimal dose for targeted oncology therapeutics is often not the maximum tolerated dose. Pharmacokinetic/pharmacodynamic (PK/PD) modeling can be an effective tool to integrate clinical data to help identify the optimal dose. This case study shows the utility of population PK/PD modeling in selecting the recommended dose for expansion (RDE) for the first-in-patient (FIP) study of PF-06939999, a small-molecule inhibitor of protein arginine methyltransferase 5. In the dose escalation part of the FIP trial (NCT03854227), 28 patients with solid tumors were administered PF-06939999 at 0.5 mg, 4 mg, 6 mg, or 8 mg once daily (q.d.) or 0.5 mg, 1 mg, 2 mg, 4 mg, or 6 mg twice daily (b.i.d.). Tolerability, safety, PK, PD biomarkers (plasma symmetrical dimethyl-arginine [SDMA]), and antitumor response were assessed. Semimechanistic population PK/PD modeling analyses were performed to characterize the time-courses of plasma PF-06939999 concentrations, plasma SDMA, and platelet counts collected from 28 patients. Platelet counts were evaluated because thrombocytopenia was the treatment-related adverse event with clinical safety concern. The models adequately described the PK, SDMA, and platelet count profiles both at individual and population levels. Simulations suggested that among a range of dose levels, 6 mg q.d. would yield the optimal balance between achieving the PD target (i.e., 78% reduction in plasma SDMA) and staying below an acceptable probability of developing grade ≥3 thrombocytopenia. As a result, 6 mg q.d. was selected as the RDE. The model-informed drug development approach informed the rational dose selection for the early clinical development of PF-06939999.
靶向肿瘤治疗药物的最佳剂量通常不是最大耐受剂量。药代动力学/药效学（PK/PD）建模可以作为一种有效的工具，用于整合临床数据，帮助确定最佳剂量。本案例研究展示了群体 PK/PD 建模在选择 PF-06939999 首次入组患者（FIP）研究扩展推荐剂量（RDE）中的应用，PF-06939999 是一种蛋白精氨酸甲基转移酶 5 的小分子抑制剂。在 FIP 试验的剂量递增部分（NCT03854227）中，28 名实体瘤患者接受了 0.5mg、4mg、6mg 或 8mg 每日一次（qd）或 0.5mg、1mg、2mg、4mg 或 6mg 每日两次（bid）的 PF-06939999 治疗。评估了耐受性、安全性、PK、PD 生物标志物（血浆对称二甲基精氨酸[SDMA]）和抗肿瘤反应。对从 28 名患者中采集的血浆 PF-06939999 浓度、血浆 SDMA 和血小板计数的时间过程进行了半机理群体 PK/PD 建模分析。评估血小板计数是因为血小板减少症是具有临床安全隐患的治疗相关不良事件。模型在个体和群体水平上均能很好地描述 PK、SDMA 和血小板计数的特征。模拟结果表明，在一系列剂量水平中，qd 6mg 可在达到 PD 目标（即血浆 SDMA 降低 78%）和避免出现可接受的 3 级以上血小板减少症风险之间取得最佳平衡。因此，qd 6mg 被选为 RDE。该模型指导的药物开发方法为 PF-06939999 的早期临床开发提供了合理的剂量选择。
