Pharsight, A Certara Company, Marseilles, France.
Cancer Chemother Pharmacol. 2010 Nov;66(6):1141-9. doi: 10.1007/s00280-010-1449-z. Epub 2010 Sep 25.
To develop a modeling framework that simulates clinical endpoints (objective response rate and progression-free survival) to support development of motesanib. The framework was evaluated using results from a phase 2 study of motesanib in thyroid cancer.
Models of probability and duration of dose modifications and overall survival were developed using data from 93 patients with differentiated thyroid cancer and 91 patients with medullary thyroid cancer, who received motesanib 125 mg once daily. The models, combined with previously developed population pharmacokinetic and tumor growth inhibition models, were assessed in predicting dose intensity, tumor size over time, objective response rate, and progression-free survival. Dose-response simulations were performed in patients with differentiated thyroid cancer.
The predicted objective response rate and median progression-free survival in patients with differentiated thyroid cancer was 15.0% (95% prediction interval, 7.5%-23.7%) and 40 weeks (95% prediction interval, 32-49 weeks), respectively, compared with the observed objective response rate of 14.0% and median progression-free survival of 40 weeks. The simulated median objective response rate increased with motesanib starting dose from 13.5% at 100 mg once daily to 38.0% at 250 mg once daily. However, simulated median progression-free survival was independent of starting dose, ranging from 40.5 weeks (95% prediction interval, 38.6-46.9 weeks) at 100 mg once daily to 40.0 weeks (95% prediction interval, 38.6-46.8 weeks) at 250 mg once daily.
Dose-response simulations confirmed the appropriateness of 125-mg once-daily dosing; no clinically relevant improvement in progression-free survival would be obtained by dose intensification. This modeling framework represents an important tool to simulate clinical response and support clinical development decisions.
开发一种能够模拟临床终点（客观缓解率和无进展生存期）的建模框架，以支持莫特塞尼布的开发。该框架使用莫特塞尼布治疗甲状腺癌的 2 期研究结果进行了评估。
使用接受莫特塞尼布 125mg 每日 1 次治疗的 93 例分化型甲状腺癌患者和 91 例甲状腺髓样癌患者的数据，开发了剂量调整概率和持续时间模型以及总生存模型。将这些模型与之前开发的群体药代动力学和肿瘤生长抑制模型相结合，用于预测剂量强度、随时间推移的肿瘤大小、客观缓解率和无进展生存期。在分化型甲状腺癌患者中进行了剂量反应模拟。
预测的分化型甲状腺癌患者的客观缓解率和中位无进展生存期分别为 15.0%（95%预测区间，7.5%-23.7%）和 40 周（95%预测区间，32-49 周），而观察到的客观缓解率和中位无进展生存期分别为 14.0%和 40 周。随着莫特塞尼布起始剂量从 100mg 每日 1 次增加到 250mg 每日 1 次，模拟的中位客观缓解率从 13.5%增加到 38.0%。然而，模拟的中位无进展生存期与起始剂量无关，从 100mg 每日 1 次的 40.5 周（95%预测区间，38.6-46.9 周）到 250mg 每日 1 次的 40.0 周（95%预测区间，38.6-46.8 周）。
剂量反应模拟证实了 125mg 每日 1 次的剂量是合适的；增加剂量不会改善无进展生存期，也不会带来临床相关获益。该建模框架代表了一种重要的工具，可以模拟临床反应并支持临床开发决策。
