Authors' Affiliations: Discovery Oncology;
Drug Metabolism and Pharmacokinetics; and.
Clin Cancer Res. 2014 Jul 15;20(14):3742-52. doi: 10.1158/1078-0432.CCR-14-0460. Epub 2014 May 8.
Antitumor clinical activity has been demonstrated for the MDM2 antagonist RG7112, but patient tolerability for the necessary daily dosing was poor. Here, utilizing RG7388, a second-generation nutlin with superior selectivity and potency, we determine the feasibility of intermittent dosing to guide the selection of initial phase I scheduling regimens.
A pharmacokinetic-pharmacodynamic (PKPD) model was developed on the basis of preclinical data to determine alternative dosing schedule requirements for optimal RG7388-induced antitumor activity. This PKPD model was used to investigate the pharmacokinetics of RG7388 linked to the time-course of the antitumor effect in an osteosarcoma xenograft model in mice. These data were used to prospectively predict intermittent and continuous dosing regimens, resulting in tumor stasis in the same model system.
RG7388-induced apoptosis was delayed relative to drug exposure with continuous treatment not required. In initial efficacy testing, daily dosing at 30 mg/kg and twice a week dosing at 50 mg/kg of RG7388 were statistically equivalent in our tumor model. In addition, weekly dosing of 50 mg/kg was equivalent to 10 mg/kg given daily. The implementation of modeling and simulation on these data suggested several possible intermittent clinical dosing schedules. Further preclinical analyses confirmed these schedules as viable options.
Besides chronic administration, antitumor activity can be achieved with intermittent schedules of RG7388, as predicted through modeling and simulation. These alternative regimens may potentially ameliorate tolerability issues seen with chronic administration of RG7112, while providing clinical benefit. Thus, both weekly (qw) and daily for five days (5 d on/23 off, qd) schedules were selected for RG7388 clinical testing.
MDM2 拮抗剂 RG7112 已显示出抗肿瘤的临床活性，但由于必要的每日剂量，患者的耐受性较差。在这里，我们利用第二代具有更高选择性和效力的 nutlin RG7388，确定间歇性给药的可行性，以指导选择初始 I 期方案。
根据临床前数据开发了药代动力学-药效学（PKPD）模型，以确定最佳 RG7388 诱导抗肿瘤活性的替代给药方案要求。该 PKPD 模型用于研究与骨肉瘤异种移植模型中抗肿瘤作用的时间过程相关的 RG7388 药代动力学。这些数据用于前瞻性预测在相同模型系统中导致肿瘤停滞的间歇性和连续给药方案。
与连续治疗相比，RG7388 诱导的细胞凋亡延迟，不需要连续治疗。在最初的疗效测试中，每天 30mg/kg 给药和每周两次 50mg/kg 给药在我们的肿瘤模型中统计学上等效。此外，每周 50mg/kg 给药等效于每天 10mg/kg 给药。对这些数据进行建模和模拟表明，可能存在几种间歇性临床给药方案。进一步的临床前分析证实了这些方案是可行的选择。
除了慢性给药外，通过建模和模拟预测，RG7388 的间歇性方案也可以实现抗肿瘤活性。这些替代方案可能潜在地改善 RG7112 慢性给药时出现的耐受性问题，同时提供临床益处。因此，选择每周（qw）和每天连续 5 天（qd5/23 停药）方案用于 RG7388 的临床测试。
